exon 19 deletion (t751 i759>s) gilotrif® (afatinib) sample · 2020. 3. 26. · egfr exon 19...

EGFR exon 19 deletion (T751_I759>S)

CDx Associated FindingsGENOMIC FINDINGS DETECTED FDFDAA-APPR-APPROOVED THERVED THERAPEUTIC OPAPEUTIC OPTIONSTIONS

Gilotrif® (Afatinib)Iressa® (Gefitinib)Tarceva® (Erlotinib)

OOTHER ALTHER ALTERATERATIONS & BIOMARKERS IDENTIFIEDTIONS & BIOMARKERS IDENTIFIED

Results reported in this section are not prescriptive or conclusive for labeled use of any specific therapeutic product. Seeprofessional services section for additional information.

MicrMicroossatatellitellite se sttatusatus MS-Stable §

TTumor Mutumor Mutation Buration Burdenden 5.04 Muts/Mb §

CDKN2ACDKN2A loss §

CDKN2BCDKN2B loss §

EEGFRGFR amplification §

ERBB3ERBB3 P1212S

METMET T263MMMTTAPAP loss §

NFKBIANFKBIA amplification §

NKNKX2X2--11 amplification §

TP53TP53 R282G

§ Refer to appendix for limitation statements related to detection of any copy number alterations, gene rearrangements, MSI or TMB result in this section.

Please refer to appendix for Explanation of Clinical Significance Classification and for variants of unknown significance (VUS).

FoundationOne CDx™ (F1CDx) is a next generation sequencing basedin vitro diagnostic device for detection of substitutions, insertion anddeletion alterations (indels), and copy number alterations (CNAs) in324 genes and select gene rearrangements, as well as genomicsignatures including microsatellite instability (MSI) and tumormutational burden (TMB) using DNA isolated from formalin-fixedparaffin embedded (FFPE) tumor tissue specimens. The test isintended as a companion diagnostic to identify patients who maybenefit from treatment with the targeted therapies listed in Table 1 inaccordance with the approved therapeutic product labeling.Additionally, F1CDx is intended to provide tumor mutation profiling tobe used by qualified health care professionals in accordance withprofessional guidelines in oncology for patients with solid malignantneoplasms. The F1CDx assay is a single-site assay performed atFoundation Medicine, Inc.

TABLE 1

INDICATIONS BIOMARKER THERAPY

EGFR exon 19 deletions and EGFR exon 21 L858R alterations Gilotrif® (Afatinib), Iressa® (Gefitinib), or Tarceva® (Erlotinib)

EGFR exon 20 T790M alterations Tagrisso® (Osimertinib)

ALK rearrangements Alecensa® (Alectinib), Xalkori® (Crizotinib), or Zykadia® (Ceritinib)

Non-small celllung cancer(NSCLC)

BRAF V600E Tafinlar® (Dabrafenib) in combination with Mekinist® (Trametinib)

BRAF V600E Tafinlar® (Dabrafenib) or Zelboraf® (Vemurafenib)

MelanomaBRAF V600E or V600K Mekinist® (Trametinib) or Cotellic® (Cobimetinib) in combination with Zelboraf®

(Vemurafenib)

Breast cancer ERBB2 (HER2) amplification Herceptin® (Trastuzumab), Kadcyla® (Ado-trastuzumab emtansine), or Perjeta®(Pertuzumab)

KRASwild-type (absence of mutations in codons 12 and 13) Erbitux® (Cetuximab)Colorectalcancer KRASwild-type (absence of mutations in exons 2, 3, and 4) and

NRASwild type (absence of mutations in exons 2, 3, and 4) Vectibix® (Panitumumab)

Ovarian cancer BRCA1/2 alterations Rubraca® (Rucaparib)

TUMOR TYPE QRF#PATIENT

Lung adenocarcinoma

PPAATIENTTIENT PHYPHYSICIANSICIAN SPECIMENSPECIMEN

DISEASE Lung adenocarcinoma NAME DATE OF BIRTH SEX MEDICAL RECORD #

ORDERING PHYSICIAN MEDICAL FACILITY ADDITIONAL RECIPIENT MEDICAL FACILITY ID PATHOLOGIST

SPECIMEN SITE SPECIMEN ID SPECIMEN TYPE DATE OF COLLECTION SPECIMEN RECEIVED

ABOUT THE TESABOUT THE TESTT FoundationOne CDx™ is the first FDA-approved broad companion diagnostic for solid tumors.

Electronically signed by Shakti Ramkissoon, M.D., Ph.D. | Jeffrey Ross, M.D., Medical Director Foundation Medicine, Inc. | 1.888.988.3639

Sample PSample Prrepareparaation:tion: 150 Second St., 1st Floor, Cambridge, MA 02141 ·· CLIA: 22D2027531Sample AnalySample Analysis:sis: 150 Second St., 1st Floor, Cambridge, MA 02141 ·· CLIA: 22D2027531

FDA APPROVED CLAIMS - PAGE 1 of 1

SAMPLE

Interpretive content on this page and subsequentpages is provided as a professional service, and isnot reviewed or approved by the FDA.

PPAATIENTTIENT

DISEASE Lung adenocarcinoma NAME DATE OF BIRTH SEX MEDICAL RECORD #

PHYPHYSICIANSICIANORDERING PHYSICIAN MEDICAL FACILITY ADDITIONAL RECIPIENT MEDICAL FACILITY IDPATHOLOGIST

SPESPECIMENCIMEN

SPECIMEN SITE SPECIMEN ID SPECIMEN TYPE DATE OF COLLECTION SPECIMEN RECEIVED

Biomarker FindingsMicrMicrosatosatellitellite Statuse Status -- MS-StableTTumor Mutation Burumor Mutation Burdenden -- TMB-Low (5 Muts/Mb)

Genomic FindingsFor a complete list of the genes assayed, please refer to the Appendix.

EEGFRGFR amplification, eamplification, exxon 19 deletion (T7on 19 deletion (T7551_I71_I7559>S9>S))ERBB3ERBB3 P1212SP1212SMETMET T2T263M63M -- subclonalsubclonal ††CDKN2A/BCDKN2A/B loslosssMMTTAPAP loslosssNFKBIANFKBIA amplificationamplificationNKNKX2X2--11 amplificationamplificationTP53TP53 R28R282G2G

66 Disease rDisease releelevvant gant geneenes with no rs with no reporeportable alttable altereraations:tions: KRKRAASS, ALK, ALK, BR, BRAFAF, RET, RET,,ERBB2ERBB2, R, ROOS1S1

† See About the Test in appendix for details.

55 TTherherapies with Capies with Clinical Benefitlinical Benefit in patient’s tumor type

88 TTherherapies with Capies with Clinical Benefitlinical Benefit in other tumor type

2525 CClinical Tlinical Trialsrials

BIOMARKER FINDINGSBIOMARKER FINDINGS AACTIONABILITYCTIONABILITY

Microsatellite status - MS-Stable No therNo therapies or clinical trials.apies or clinical trials. see Biomarker Findings section

Tumor Mutation Burden - TMB-Low (5Muts/Mb)

No therNo therapies or clinical trials.apies or clinical trials. see Biomarker Findings section

GENOMIC FINDINGSGENOMIC FINDINGS THERAPIES WITH CLINICAL BENEFITTHERAPIES WITH CLINICAL BENEFIT(IN P(IN PAATIENT’TIENT’S TUS TUMOR TYPE)MOR TYPE)

THERAPIES WITH CLINICAL BENEFITTHERAPIES WITH CLINICAL BENEFIT(IN O(IN OTHER TUTHER TUMOR TYPE)MOR TYPE)

EGFR - amplification, exon 19 deletion(T751_I759>S)

10 T10 Trialsrials see psee p.. 1515

Afatinib

Erlotinib

Gefitinib

Osimertinib

Cetuximab

Lapatinib

Panitumumab

ERBB3 - P1212S


Afatinib Ado-trastuzumab emtansine

Lapatinib

Pertuzumab

Trastuzumab

Trastuzumab-dkst

MET - T263M


Crizotinib Cabozantinib


Lung adenocarcinoma

The content provided as a professional service by Foundation Medicine, Inc., has not been reviewed or approved by the FDA.



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GENOMIC FINDINGS AND BIOMARKERS WITH NO REPORTABLE THERAPEUTIC OR CLINICAL TRIAL OPTIONS

For more information regarding biological and clinical significance, including prognostic, diagnostic, germline, and potential chemosensitivityimplications, see the Genomic Alterations section.

Note: Genomic alterations detected may be associated with activity of certain FDA approved drugs; however, the agents listed in this report may have varied clinical evidence in the patient’s tumor type. Neither thetherapeutic agents nor the trials identified are ranked in order of potential or predicted efficacy for this patient, nor are they ranked in order of level of evidence for this patient’s tumor type.

p. 5

p. 6

p. 6

p. 7

p. 7

CDKN2A/B loss

MTAP loss

NFKBIA amplification

NKX2-1 amplification

TP53 R282G


Lung adenocarcinoma


Electronically signed by Shakti Ramkissoon, M.D., Ph.D. | Jeffrey Ross, M.D., Medical DirectorFoundation Medicine, Inc. | 1.888.988.3639



SAMPLE

BIOMARKERBIOMARKER

Microsatellite statusCACATEGORTEGORYY

MS-Stable

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESOn the basis of clinical evidence, MSS tumorsare significantly less likely than MSI-H tumorsto respond to anti-PD-1 immune checkpointinhibitors1-3, including approved therapiesnivolumab and pembrolizumab4-5. In aretrospective analysis of 361 patients with solidtumors treated with pembrolizumab, 3% wereMSI-H and experienced a significantly higherORR compared with non-MSI-H cases (70% vs.12%, p=0.001)6. Pembrolizumab therapyresulted in a significantly lower objective

response rate (ORR) in MSS colorectal cancer(CRC) compared with MSI-H CRC (0% vs.40%)5. Similarly, a clinical study of nivolumab,alone or in combination with ipilimumab, inpatients with CRC reported a significantlyhigher response rate in patients with MSI-Htumors than those without4.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISMSI-high (MSI-H) has been reported at variousfrequencies in non-small cell lung cancer(NSCLC) as well as in small cell lungcancer7-12. One study observed MSI-H in 0.8%(4/480) of lung adenocarcinoma cases; the MSI-H tumors occurred in patients with smokinghistory, and 3/4 MSI-H cases hadnonsynchronous carcinomas in other organs,although none of the patients were diagnosedwith Lynch syndrome7.

FINDING SUMMARFINDING SUMMARYYMicrosatellite instability (MSI) is a condition ofgenetic hypermutability that generatesexcessive amounts of short insertion/deletionmutations in the genome; it generally occurs atmicrosatellite DNA sequences and is caused bya deficiency in DNA mismatch repair (MMR) inthe tumor13. Defective MMR and consequentMSI occur as a result of genetic or epigeneticinactivation of one of the MMR pathwayproteins, primarily MLH1, MSH2, MSH6, orPMS213-15. The tumor seen here ismicrosatellite-stable (MSS), equivalent to theclinical definition of an MSS tumor: one withmutations in none of the tested microsatellitemarkers16-18. MSS status indicates MMRproficiency and typically correlates with intactexpression of all MMR familyproteins13,15,17-18.

BIOMARKERBIOMARKER

Tumor MutationBurdenCACATEGORTEGORYY

TMB-Low (5 Muts/Mb)

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESOn the basis of emerging clinical evidence,increased TMB may be associated with greatersensitivity to immunotherapeutic agents,including anti-CTLA-419, anti-PD-L1 20-22,and anti-PD-1 therapies5,23-24; FDA-approvedagents include ipilimumab, atezolizumab,avelumab, durvalumab, pembrolizumab, andnivolumab. In multiple solid tumor types,higher mutational burden has correspondedwith response and improved prognosis.Pembrolizumab improved progression-freesurvival (14.5 vs. 3.4-3.7 months) in patientswith non-small cell lung cancer (NSCLC) andhigher mutational load (greater than 200nonsynonymous mutations; hazard ratio =0.19)24. In studies of patients with eitherNSCLC or colorectal cancer (CRC), patientswhose tumors harbor elevated mutationalburden reported higher overall response ratesto pembrolizumab5,23-24. Anti-PD-1 therapieshave achieved clinical benefit for certainpatients with high mutational burden,including 3 patients with endometrial

adenocarcinoma who reported sustained partialresponses following treatment withpembrolizumab25 or nivolumab26, a patientwith hypermutant glioblastoma who obtainedclinical benefit from pembrolizumab27, and twopediatric patients with biallelic mismatch repairdeficiency (bMMRD)-associatedultrahypermutant glioblastoma whoexperienced clinically and radiologicallysignificant responses to nivolumab28. Inpatients with melanoma, mutational load wasassociated with long-term clinical benefit fromipilimumab19,29 and anti-PD-1/anti-PD-L1treatments21. For patients with metastaticurothelial carcinoma, those who responded toatezolizumab treatment had a significantlyincreased mutational load [12.4 mutations(muts) per megabase (Mb)] compared tononresponders (6.4 muts/Mb)20, andmutational load of 16 muts/Mb or higher wasassociated with significantly longer overallsurvival22.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISLow TMB is observed more commonly in non-small cell lung carcinomas (NSCLC) harboringknown driver mutations (EGFR, ALK, ROS1, orMET) with the exception of BRAF or KRASmutations, which are observed inapproximately half of intermediate-high TMBcases30. Although some studies have reported alack of association between smoking and

mutational burden in NSCLC31-33, severalother large studies did find a strong associationwith increased TMB34-37. A large study ofChinese patients with lung adenocarcinomareported a shorter median overall survival (OS)for tumors with a higher number of mutationsin a limited gene set compared with lowermutation number (48.4 vs. 61.0 months)32.

FINDING SUMMARFINDING SUMMARYYTumor mutation burden (TMB, also known asmutation load) is a measure of the number ofsomatic protein-coding base substitution andinsertion/deletion mutations occurring in atumor specimen. TMB is affected by a variety ofcauses, including exposure to mutagens such asultraviolet light in melanoma38-39 andcigarette smoke in lung cancer24,40, mutationsin the proofreading domains of DNApolymerases encoded by the POLE and POLD1genes41-45, and microsatellite instability(MSI)41,44-45. The tumor seen here harbors alow TMB. Compared to patients with tumorsharboring higher TMB levels, patients withtumors harboring low TMB levels haveexperienced lower rates of clinical benefit fromtreatment with immune checkpoint inhibitors,including anti-CTLA-4 therapy in melanoma19,anti-PD-L1 therapy in urothelial carcinoma20,and anti-PD-1 therapy in non-small cell lungcancer and colorectal cancer5,24.


Lung adenocarcinoma

BIOMARKER FINDINGBIOMARKER FINDINGSS





SAMPLE

GENEGENE

EGFRALALTERATERATIONTION

amplification, exon 19deletion (T751_I759>S)

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESEGFR activating mutations or amplificationmay predict sensitivity to EGFR inhibitorsincluding erlotinib, gefitinib, afatinib,osimertinib, cetuximab, panitumumab, andlapatinib46-50. Other EGFR-targeted therapiesare also in clinical trials. A Phase 2 trial of thepan-ERBB inhibitor dacomitinib in patientswith lung adenocarcinoma reported 98% (44/45) disease control [partial response (PR) orstable disease], including a 76% PR rate, inpatients with EGFR exon 19 deletions or theL858R mutation; lower disease control and PRrates were reported in patients with otherEGFR mutations, wild-type EGFR, or unknownEGFR status51. Third-generation EGFRinhibitors, such as osimertinib or rociletinib,selectively target mutated EGFR including theEGFR resistance variant T790M. Osimertinib is

FDA approved to treat patients with EGFRT790M-positive advanced NSCLC and diseaseprogression on EGFR inhibitor therapy49.Necitumumab is an anti-EGFR antibody that isFDA approved for the treatment of metastaticsquamous NSCLC in combination withgemcitabine and cisplatin. Addition ofnecitumumab increased overall andprogression-free survival in patients withsquamous NSCLC relative to chemotherapyalone; however, it exhibited a poor tolerabilityprofile in non-squamous NSCLC, and EGFRexpression has not been demonstrated to bepredictive of clinical benefit in NSCLC52-53.HSP90 inhibitors have been clinically evaluatedfor patients with EGFR-mutated NSCLC54-58

and have shown activity against NSCLC withcertain EGFR mutations59. The reovirusReolysin, which targets cells that harboractivated RAS signaling due to alterations inRAS genes or upstream activators such asEGFR60-62, is also in clinical trials in sometumor types. Reolysin has demonstrated mixedclinical efficacy, with the highest rate ofresponse reported for head and neckcancer63-71.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSIS

Amplification of EGFR has been reported in6-42% of non-small cell lung carcinoma(NSCLC) samples72-75. EGFR mutations havebeen reported in 12-36% of lungadenocarcinoma samples, with amplificationfound in 7% of cases34,73,76, and EGFR proteinexpression/overexpression has been reportedin up to 70% of NSCLC tumors77. EGFRmutations were shown to predict survivaladvantage for patients with Stage 1-3 resectedlung adenocarcinoma or NSCLC78-79.

FINDING SUMMARFINDING SUMMARYYEGFR encodes the epidermal growth factorreceptor, which belongs to a class of proteinscalled receptor tyrosine kinases. In response tosignals from the environment, EGFR passesbiochemical messages to the cell that stimulateit to grow and divide80. Amplification of EGFRhas been associated with increased expressionof EGFR mRNA and protein in several cancertypes72,81-82. The mutation seen here is adeletion in exon 19, encoding a portion of thekinase domain of EGFR; such mutations havebeen shown to activate EGFR kinase activityand to confer sensitivity to inhibitors such aserlotinib and gefitinib83-85.

GENEGENE

ERBB3ALALTERATERATIONTION

P1212S

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESERBB3/HER3 possesses a low-activity kinasedomain and requires other ERBB familymembers for efficient signaling86-88.Therefore, ERBB3 amplification or activatingmutation may predict sensitivity to therapiestargeting ERBB2, such as pertuzumab,trastuzumab, ado-trastuzumab, lapatinib, andafatinib. In a study of afatinib monotherapy forpatients with metastatic urothelial carcinoma,patients with ERBB3 mutation or ERBB2

amplification had significantly improved overallsurvival compared to patients withoutalterations (6.6 months vs. 1.4 months)89. Apatient with HER2-negative breast cancerharboring an activating ERBB3 mutation had apartial response to the combination oftrastuzumab and lapatinib90. In preclinicalstudies, cells with ERBB3 activating mutationswere reported to be sensitive to anti-ERBB2inhibition86. Antibodies targeting ERBB3 arealso being studied in clinical trials. However, asthe mutation reported here has not beencharacterized, it is not known if thesetherapeutic approaches would be relevant.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISERBB3 mutations have been reported in up to1% of lung adenocarcinomas73,86. ERBB3

protein expression has been reported in 18%(9/51) of lung adenocarcinomas91. High-levelexpression of ERBB3 mRNA has beenassociated with distant site metastases and pooroverall survival in non-small cell lung cancer(NSCLC) patients92.

FINDING SUMMARFINDING SUMMARYYERBB3, which is also known as HER3, encodesa member of the epidermal growth factorreceptor (EGFR) family93. This ERBB3mutation has not been characterized and itseffect on ERBB3 function is unknown;however, mutation at this position has beenreported previously in the context of cancer,which may indicate biological significance.


Lung adenocarcinoma

GENOMIC FINDINGGENOMIC FINDINGSS





SAMPLE

GENEGENE

METALALTERATERATIONTION

T263M

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESStrong evidence suggests that MET activationmay predict sensitivity to targeted therapies94

such as crizotinib, FDA approved for thetreatment of ALK-positive NSCLC95, andcabozantinib, FDA approved for the treatmentof metastatic medullary thyroid cancer96.Sensitivity to crizotinib is suggested byextensive clinical data in patients with MET-amplified cancers, including non-small cell lungcancer (NSCLC)97-9899-101, gastric cancer102,gastroesophageal cancer103, glioblastoma104,and carcinoma of unknown primary105, as wellas in patients with MET-mutated cancers,including NSCLC106-110, renal cell carcinoma(RCC)111 and histiocytic sarcoma106, and inpatients with NSCLC112 and pulmonarysarcomatoid carcinoma113 whose tumorsharbored both MET mutation andamplification. Sensitivity to cabozantinib issuggested by clinical benefit derived by apatient with MET-amplified and MET-mutated

NSCLC in one case report107, as well as byextensive preclinical data114-120. Strongclinical data also suggest sensitivity of MET-altered tumors to various other MET inhibitors,with examples including AMG 337 in gastric,esophageal, or gastroesophageal junctioncancer121-122, volitinib in RCC123, tepotinib incolorectal cancer124, capmatinib in NSCLC106,MGCD265 in NSCLC125, PF-04217903 inRCC126, and foretinib in RCC127. Furthermore,the MET-targeting antibodies onartuzumab andMetMAb have elicited responses for patientswith MET-amplified NSCLC128 or gastriccancer129. In addition, high MET expressionhas been suggested to predict patient responseto therapy regimens involving rilotumumab, amonoclonal antibody that targets the METligand HGF130. However, in cases ofuncharacterized alterations, such as seen here, itis unclear whether these therapeuticapproaches would be relevant.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISIn one study of 4402 lung adenocarcinomacases, MET mutations (primarily those affectingMET exon 14 splicing) have been reported in~3% of samples106. In the TCGA datasets,MET mutation has been observed in 8.3% oflung adenocarcinomas and 2.1% of lung

squamous cell carcinomas73,131. METamplification has been reported in up to 11% ofnon-small-cell lung cancer (NSCLC) cases andhas been found to increase following treatmentwith EGFR inhibitors74,132-134. Theprognostic implications of MET amplification,gain, and/or protein overexpression in NSCLChave yielded conflicting results, with somestudies reporting no association and othersfinding a correlation with decreased survivaland poor prognosis74,132,135-138.

FINDING SUMMARFINDING SUMMARYYMET encodes a receptor tyrosine kinase, alsoknown as c-MET or hepatocyte growth factorreceptor (HGFR), that is activated by the ligandHGF; MET activation results in signalingmediated partly by the RAS-RAF-MAPK andPI3K pathways to promote proliferation94,139.Alterations such as reported here have not beencharacterized and are of unclear functionalsignificance; however, similar alterations havebeen reported in the context of cancer, whichmay indicate biological relevance. MultipleMET activating alterations have exhibitedclinical sensitivity to a variety of METinhibitors in multiple cancertypes106-111,126-127.

GENEGENE

CDKN2A/BALALTERATERATIONTION

loss

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESPreclinical data suggest that tumors with loss ofp16INK4a and p15INK4b function may besensitive to CDK4/6 inhibitors, such asabemaciclib, ribociclib, and palbociclib140-143.Although case studies have reported thatpatients with breast cancer or uterineleiomyosarcoma harboring CDKN2A lossresponded to palbociclib treatment144-145,multiple other clinical studies have shown nosignificant correlation between p16INK4a lossor inactivation and therapeutic benefit of theseagents146-147 148-152; it is not knownwhether CDK4/6 inhibitors would be

beneficial in this case. Although preclinicalstudies have suggested that loss of p14ARFfunction may be associated with reducedsensitivity to MDM2 inhibitors153-154, theclinical relevance of p14ARF as a predictivebiomarker is not clear.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISCDKN2A/B loss or mutation has been reportedin 19% and 4% of lung adenocarcinomas,respectively73. Loss of p16INK4a proteinexpression, through CDKN2A mutation,homozygous deletion, or promoter methylation,has been described in 49-68% of non-small celllung cancer (NSCLC) samples, whereas lowp14ARF protein expression has been detectedin 21-43% of NSCLC samples155-159. Loss ofp16INK4a protein as well as CDKN2Apromoter hypermethylation correlate with poorsurvival in patients with NSCLC156,160-162.

FINDING SUMMARFINDING SUMMARYYCDKN2A encodes two different, unrelatedtumor suppressor proteins, p16INK4a andp14ARF, whereas CDKN2B encodes the tumorsuppressor p15INK4b163-164. Both p15INK4band p16INK4a bind to and inhibit CDK4 andCDK6, thereby maintaining the growth-suppressive activity of the Rb tumorsuppressor; loss or inactivation of eitherp15INK4b or p16INK4a contributes todysregulation of the CDK4/6-cyclin-Rbpathway and loss of cell cycle control155,165.The tumor suppressive functions of p14ARFinvolve stabilization and activation of p53, via amechanism of MDM2 inhibition166-167. Thisalteration is predicted to inactivatep16INK4a168-171, p15INK4b172, andp14ARF173-174.


Lung adenocarcinoma






SAMPLE

GENEGENE

MTAPALALTERATERATIONTION

loss

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESInactivation of MTAP is being explored forspecific metabolic vulnerabilities. In preclinicalcancer models, MTAP inactivation showedincreased sensitivity to inhibitors of purinesynthesis or purine analogs, especially uponaddition of exogenous MTA, which is convertedto adenine in normal cells, providingcompetition to purine poisons lacking inMTAP-deficient cells175-183. However, suchcombination approaches are not being clinicallytested, and a Phase 2 study of L-alanosine, aninhibitor of adenine synthesis, as amonotherapy in 65 patients with MTAP-deficient cancers reported no responses andstable disease in 24% of patients184. Other

approaches have been described in preclinicalstudies185-187, but these have not beenclinically tested.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISMTAP loss/homozygous deletion as well asloss of expression has been reported in a widevariety of solid tumors and hematologiccancers188-189; such events have beencorrelated with poor prognosis in a variety ofcancer types, including hepatocellularcarcinoma190, gastrointestinal stromaltumors191, mantle cell lymphoma (MCL)192,melanoma193-194, gastric cancer195,myxofibrosarcoma196, nasopharyngealcarcinoma197, ovarian carcinoma188 and non-small cell lung cancer198. MTAP loss was notprognostic in pediatric B-cell acute lymphocyticleukemia199 or in astrocytoma200. However,MTAP has also been reported to beoverexpressed in colorectal cancer (CRC)samples201, and MTAP retention is thought tobe important for prostate cancer growth due to

continuous supply of SAM202. Germline SNPsin MTAP have been correlated with thedevelopment of cutaneous melanoma203-204,esophageal cancer205-206, osteosarcoma207,and CRC208.

FINDING SUMMARFINDING SUMMARYYMTAP encodes S-methyl-5'-thioadenosine(MTA) phosphorylase, a tumor suppressorinvolved in polyamine metabolism andmethionine synthesis, although its enzymaticfunction is dispensable for its tumor suppressoractivity209-210. Decreased expression ofMTAP leads to MTA accumulation withintumor cells and theirmicroenvironment190,211-212, therebyreducing intracellular argininemethylation185-187 and altering cellsignaling212-213. MTAP is located at 9p21,adjacent to CDKN2A and CDKN2B, with whichit is frequently co-deleted in various cancers.Other alterations in MTAP are rare and havenot been extensively characterized.

GENEGENE

NFKBIAALALTERATERATIONTION

amplification

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESThere are no therapies that directly targetNFKBIA amplification or expression.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISIn the TCGA datasets, amplification of NFKBIAhas been reported with the highest incidence in

lung adenocarcinoma (11.7%)73, esophagealcarcinoma (3.8%), uterine carcinosarcoma(3.6%), lung squamous cell carcinoma (3.4%),and ovarian serous cystadenocarcinoma (2.6%)(cBioPortal, 2017). Amplification or increasedexpression of NFKBIA in EGFR-mutant lungcancer has been reported to predict improvedresponse to EGFR tyrosine kinaseinhibitors214-215. Certain NFKBIApolymorphisms, which may affect IkBaexpression levels, have been studied as riskfactors for some cancer types, although the dataare mixed and conflicting216-218.

FINDING SUMMARFINDING SUMMARYY

NFKBIA encodes IkBa, an inhibitor of the NF-kappaB (NFkB)/REL complex. It has beenreported to act as a tumor suppressor inHodgkin’s lymphoma219-223 and inglioblastoma216,224-225. NFKBIA has beenreported to be amplified in cancer226 and maybe biologically relevant in this context227-228.In contrast, truncating mutations that result inloss of the majority of the IkBa protein arepredicted to be inactivating.


Lung adenocarcinoma






SAMPLE

GENEGENE

NKX2-1ALALTERATERATIONTION

amplification

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESThere are no approved therapies or trials thattarget tumors with TTF-1 amplification oroverexpression. Lung cancer cell lines thatexpress both TTF-1 and NKX2-8, which islocated in the same amplicon as NKX2-1, havedemonstrated resistance to cisplatintherapy229, although conflicting data has alsobeen reported230.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISPutative amplification of NKX2-1 has beenreported with the highest incidence in lungcancer, and has been observed in 14% ofadenocarcinomas73 and 5% of squamous cellcarcinomas (SCC)131 as well as other tumortypes including prostate adenocarcinomas(6%)231, and poorly differentiated andanaplastic thyroid cancers (4%)232. NKX2-1mutation has been observed in 9% of acinar cellcarcinomas of the pancreas233, 5% of uterinecarcinosarcomas234, and is infrequent in othertumor types (cBioPortal, COSMIC, 2017). TTF-1is expressed in a majority of lungadenocarcinomas and small cell carcinomas, aswell as in a subset of thyroid and CNS

tumors235-237. Cytoplasmic TTF-1 expressionhas been reported as an adverse prognosticfactor in breast carcinoma238-239. However,whether amplification and/or expression statusof NKX2-1 have prognostic implications forpatients with lung cancer iscontroversial229-230,240-243. TTF-1 has beenobserved to have tumor-promoting as well asanti-oncogenic roles244-245.

FINDING SUMMARFINDING SUMMARYYNKX2-1 (NK2 homeobox 1) encodes the thyroidtranscription factor TTF-1246. Amplification ofNKX2-1 results in overexpression of TTF-1 andupregulated transcription of downstream targetgenes247.

GENEGENE

TP53ALALTERATERATIONTION

R282G

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESThere are no approved therapies to addressTP53 mutation or loss. However, tumors withTP53 loss of function alterations may besensitive to the WEE1 inhibitorAZD1775248-251, therapies that reactivatemutant p53 such as APR-246252-255, or p53gene therapy and immunotherapeutics such asSGT-53256-260 and ALT-801261. In a Phase 1study, AZD1775 in combination withgemcitabine, cisplatin, or carboplatin elicitedpartial response in 10% (17/176) and stabledisease in 53% (94/176) of patients with solidtumors; the response rate was 21% (4/19) inpatients with TP53 mutations versus 12% (4/33)in patients who were TP53-wild-type262.Combination of AZD1775 with paclitaxel andcarboplatin achieved significantly longerprogression-free survival than paclitaxel andcarboplatin alone in patients with TP53-mutantovarian cancer263. Furthermore, AZD1775 incombination with carboplatin achieved a 27%(6/22) response rate and 41% (9/22) stabledisease rate in patients with TP53-mutant

ovarian cancer refractory or resistant tocarboplatin plus paclitaxel264. In a Phase 1btrial in patients with p53-positive high-gradeserous ovarian cancer, APR-246 combined withcarboplatin and pegylated liposomaldoxorubicin achieved a 52% (11/21) responserate and 100% disease control rate252. In aPhase 1b clinical trial of SGT-53 in combinationwith docetaxel in patients with solid tumors,75% (9/12) of evaluable patients experiencedclinical benefit, including two confirmed andone unconfirmed partial responses and twoinstances of stable disease with significanttumor shrinkage260. Additionally, thecombination of a CHK1 inhibitor andirinotecan reportedly reduced tumor growthand prolonged survival in a TP53 mutant, butnot TP53 wild-type, breast cancerxenotransplant mouse model265. Kevetrin hasalso been reported to activate p53 in preclinicalstudies and might be relevant in the context ofmutant p53266. Clinical trials of these agentsare under way for some tumor types forpatients with a TP53 mutation.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISTP53 is one of the most commonly mutatedgenes in lung cancer. TP53 mutations have beenreported in 43-80% of non-small cell lungcancers (NSCLCs)73,131,158,267-271. Mutationsin TP53 have been associated with lymph node

metastasis in patients with lungadenocarcinoma272. In one study of 55 patientswith lung adenocarcinoma, TP53 alterationscorrelated with immunogenic featuresincluding PD-L1 expression, tumor mutationburden and neoantigen presentation; likely as aconsequence of this association TP53 mutationscorrelated with improved clinical outcomes toPD-1 inhibitors pembrolizumab and nivolumabin this study23.

FINDING SUMMARFINDING SUMMARYYFunctional loss of the tumor suppressor p53,which is encoded by the TP53 gene, is commonin aggressive advanced cancers273. Anyalteration that results in the disruption orpartial or complete loss of the region encodingthe TP53 DNA-binding domain (DBD, aa100-292) or the tetramerization domain (aa325-356), such as observed here, is thought todysregulate the transactivation ofp53-dependent genes and is predicted topromote tumorigenesis274-276. Germlinemutations in TP53 are associated with the veryrare disorder Li-Fraumeni syndrome and theearly onset of many cancers277-282. Estimatesfor the prevalence of germline TP53 mutationsin the general population range from1:5,000283 to 1:20,000282, and in theappropriate clinical context, germline testing ofTP53 is recommended.


Lung adenocarcinoma






SAMPLE

AAffatinibatinibAssay findings association

EEGFRGFRERBB3ERBB3P1212S

APPROAPPROVED INDICAVED INDICATIONSTIONSAfatinib is an irreversible kinase inhibitor that targets thekinase domains of EGFR, ERBB2/HER2, and ERBB4. It isFDA approved for the first-line treatment of patients withmetastatic non-small cell lung cancer (NSCLC) andnonresistant EGFR mutations and for the treatment ofpatients with metastatic, squamous NSCLC afterprogression on platinum-based chemotherapy.

GENE AGENE ASSSOCIASOCIATIONTIONActivation or amplification of EGFR may indicatesensitivity to afatinib. In Phase 2 studies of afatinib,patients with EGFR-amplified NSCLC achieved anobjective response rate of 20% (5/25) and a disease-control rate of 64% (16/25)284, and 2/5 patients withEGFR amplification in other solid tumors experiencedstable disease285. ERBB3/HER3 possesses a low-activitykinase domain and requires other ERBB family membersfor efficient signaling, ERBB2/HER2 inparticular86-88,286; therefore, ERBB3 amplification oractivating mutations may indicate sensitivity to therapiessuch as afatinib. Partial response (PR) or stable disease(SD) was elicited in 5/7 patients with urothelial carcinomaharboring ERBB3 mutations (V104M, R103G, or G284R)and/or HER2 copy number gain treated with afatinib89.

SUPPORTING DSUPPORTING DAATTAAPhase 3 clinical trials have demonstrated that treatmentwith afatinib, compared with chemotherapy, leads tosignificantly increased progression-free survival (PFS) forpatients with EGFR-mutant NSCLC48,287 and increased

overall survival (OS) for patients with EGFR exon 19alterations specifically288. A Phase 3 trial comparingafatinib with erlotinib as second-line therapies foradvanced lung squamous cell carcinoma reportedsignificantly higher OS (7.9 months vs. 6.8 months) anddisease control rate (DCR) (51% vs. 40%) for patientstreated with afatinib289. A Phase 2b trial comparingafatinib with gefitinib in patients with EGFR-mutantNSCLC reported similar OS (27.9 months vs. 24.5months), but significantly higher time-to-treatmentfailure (13.7 months vs. 11.5 months), and overall responserate (73% vs. 56%)290. Phase 2/3 studies of afatinibtreatment for patients with erlotinib- or gefitinib-resistant NSCLC have generally reported partialresponses (PRs) of only 7–9%291-296 and DCRs of morethan 50%295; in particular, disease control was achievedfor 2/2 patients with EGFR-amplified NSCLC295 and 9/14 patients with T790M-positive NSCLC296. The T790Mmutation has been implicated in reduced response toafatinib294,297-299, with a secondary T790M mutationreported in 48% (20/42) of patients with afatinib-resistant lung adenocarcinoma297. The combination ofafatinib with cetuximab resulted in a higher response rate(29%) for patients with erlotinib- or gefitinib-resistantdisease300, including T790M-positive cases300-301,although adverse reactions may be a concern with thiscombination302. Upon progression on afatinib, furtherbenefit has been reported from combination treatmentwith afatinib and paclitaxel303 and with afatinib andcetuximab304.


Lung adenocarcinoma

IN PIN PAATIENT'S TUTIENT'S TUMOR TMOR TYPEYPETHERTHERAPIES WITH CLINICAPIES WITH CLINICAL BENEFITAL BENEFIT





SAMPLE

CrizCrizotinibotinibAssay findings association

METMETT263M

APPROAPPROVED INDICAVED INDICATIONSTIONSCrizotinib is an inhibitor of the kinases MET, ALK, ROS1,and RON. It is FDA approved to treat patients withmetastatic non-small cell lung cancer (NSCLC) whosetumors are positive for ALK rearrangements or ROS1rearrangements.

GENE AGENE ASSSOCIASOCIATIONTIONSensitivity of MET alterations to crizotinib is suggestedby extensive clinical data in patients with MET-amplifiedcancers, including non-small cell lung cancer(NSCLC)97-9899-101, gastric cancer102, gastroesophagealcancer103, glioblastoma104, and carcinoma of unknownprimary105, as well as in patients with MET-mutatedcancers, including NSCLC106-110, renal cell carcinoma(RCC)111 and histiocytic sarcoma106. However, it is notknown whether this therapeutic approach would berelevant in the context of alterations that have not beenfully characterized, as seen here.

SUPPORTING DSUPPORTING DAATTAAClinical data indicate activity of crizotinib in MET-activated NSCLC, including lung adenocarcinoma andlung squamous cell carcinoma. In two ongoing studies ofcrizotinib (AcSé, NCT02034981 and PROFILE 1001,NCT00585195), 4 partial responses (PRs) and 4 stablediseases (SDs) were reported in 14 evaluable patients97,and 4 PRs were reported in 12 evaluable patients305 with

MET-amplified NSCLC. Additional patients with MET-amplified NSCLC have been reported to experienceclinical benefit from crizotinib in several casestudies99-101,306-308. A patient with lungadenocarcinoma harboring K860I and L858R EGFRmutations, who acquired both EGFR T790M and MET-amplification upon various treatments, experiencedclinical benefit from subsequent combination treatmentof osimertinib and crizotinib; this combination regimenwas well tolerated309. A case report of a patient withchemotherapy-refractory, pulmonary sacomatoidcarcinoma with a MET exon 14 splice site alteration andamplification experienced a partial response to crizotinibtreatment113. In an ongoing expansion cohort of thePROFILE 1001 study, patients with NSCLC harboringMET exon 14 alterations experienced an overall responserate of 44% to crizotinib, including 8 confirmed PRs and 9SDs out of 18 patients; treatment duration ranged from0.5 to 12.2+ months, with 76% (16/21) of patients still onstudy310. Several case studies have also reported responseto crizotinib in NSCLC with MET exon 14 alterations,with or without concomitant METamplification107-110,112,306,311-313. In patients withNSCLC and MET overexpression with or without geneamplification, crizotinib elicited 11 PRs and 3 SDs in 19evaluable patients98. However, as the mutation reportedhere has not been characterized, it is not known if thistherapeutic approach would be relevant.

ErlotinibErlotinibAssay findings association

EEGFRGFRamplification, exon 19 deletion(T751_I759>S)

APPROAPPROVED INDICAVED INDICATIONSTIONSErlotinib is a small molecule inhibitor of EGFR. It is FDAapproved both as first-line and maintenance therapy, aswell as second- or greater line of treatment afterchemotherapy failure, for patients with metastatic non-small cell lung cancer (NSCLC) harboring EGFR exon 19deletions or exon 21 (L858R) mutations. Erlotinib is alsoFDA approved in combination with gemcitabine as a first-line treatment for advanced pancreatic cancer.

GENE AGENE ASSSOCIASOCIATIONTIONAmplification or activation of EGFR may predictsensitivity to therapies such as erlotinib. In a prospectivestudy of advanced NSCLC treated with gefitinib (n=102),EGFR copy gain was significantly associated withimproved survival [hazard ratio (HR)=0.44]314. Severalmeta-analyses spanning 14 to 20 studies of patients withadvanced NSCLC receiving single-agent erlotinib orgefitinib (n=1725 to 1854) reported the association ofincreased EGFR copy number with improved overallsurvival (HR=0.72 to 0.77), although the survival benefitwas not observed for East Asian populations (HR=0.79 to1.11)315-317.

SUPPORTING DSUPPORTING DAATTAA

The initial approval of erlotinib in NSCLC was based onthe BR.21 Phase 3 randomized trial demonstratingprolonged overall survival for unselected patients withNSCLC treated with erlotinib compared with standardchemotherapy318. Furthermore, several randomized Phase3 trials have shown a significant improvement in responseand progression-free survival for erlotinib compared withcombination chemotherapy in patients with known EGFRmutations. This includes the EURTAC trial of erlotinibversus platinum-based chemotherapy as first-linetreatments46 and the SATURN trial of erlotinib asmaintenance therapy following first-line platinum-basedchemotherapy319. On the other hand, the efficacy oferlotinib for patients lacking the common EGFRactivating alterations (exon 19 deletion or L858Rmutation) may be regimen-dependent. For patients withNSCLC and wild-type EGFR, chemotherapy was found tobe more effective than erlotinib as first-, second-, or third-line treatment320-322. However, as maintenance therapy,erlotinib reduced risk for progression compared withplacebo by 19% (hazard ratio = 0.81)322. The single-arm,Phase IV TRUST trial for genomically unselected patientswith advanced NSCLC who failed on, or were unsuitablefor, chemotherapy or who were ineligible for erlotinibclinical trials reported a disease control rate of 69%323.


Lung adenocarcinoma






SAMPLE

GefitinibGefitinibAssay findings association


APPROAPPROVED INDICAVED INDICATIONSTIONSGefitinib targets the tyrosine kinase EGFR and is FDAapproved to treat non-small cell lung cancer (NSCLC)harboring exon 19 deletions or exon 21 (L858R)substitution mutations in EGFR.

GENE AGENE ASSSOCIASOCIATIONTIONAmplification or activation of EGFR may predictsensitivity to therapies such as gefitinib. In a prospectivestudy of advanced NSCLC treated with gefitinib (n=102),EGFR copy gain was significantly associated withimproved survival [hazard ratio (HR)=0.44]314. Severalmeta-analyses spanning 14 to 20 studies of patients withadvanced NSCLC receiving single-agent erlotinib orgefitinib (n=1725 to 1854) reported the association ofincreased EGFR copy number with improved overall

survival (HR=0.72 to 0.77), although the survival benefitwas not observed for East Asian populations (HR=0.79 to1.11)315-317.

SUPPORTING DSUPPORTING DAATTAAGefitinib achieved an objective response rate of 69.8% andan overall survival of 19.2 months as first-line treatmentof Caucasian patients with NSCLC and EGFR sensitizingmutations, which were mostly EGFR exon 19 deletionsand EGFR L858R47. In the retrospective analysis of aPhase 3 study in Asia, gefitinib increased progression-freesurvival in a subgroup of patients with EGFR mutation-positive NSCLC as compared with carboplatin/paclitaxeldoublet chemotherapy (hazard ratio for progression0.48)324-325.

OsimerOsimertinibtinibAssay findings association


APPROAPPROVED INDICAVED INDICATIONSTIONSOsimertinib is an irreversible EGFR tyrosine kinaseinhibitor (TKI) that is selective for EGFR TKI-sensitizingmutations and the EGFR T790M mutation. It is FDAapproved to treat patients with metastatic EGFR T790M-positive non-small cell lung cancer (NSCLC) and diseaseprogression on or after EGFR TKI therapy.

GENE AGENE ASSSOCIASOCIATIONTIONEGFR TKI-sensitizing mutations and/or the EGFRT790M mutation may predict sensitivity toosimertinib49,326. T790M-positive patients showedhigher response rates than T790M-negative cases in aPhase 1 study for patients with acquired EGFR TKIresistance (61% vs. 21%)49. Although tumors with EGFRamplification may not be sensitive to osimertinib, whichselectively targets mutated EGFR, preclinical data indicatesensitivity of various activating EGFR alterations toosimertinib326.

SUPPORTING DSUPPORTING DAATTAAOsimertinib has been studied primarily for the treatmentof EGFR-mutated NSCLC. In a Phase 3 study for patientswith EGFR T790M-positive advanced NSCLC whoprogressed on EGFR tyrosine kinase inhibitor (TKI)therapy, osimertinib compared with combinationplatinum therapy led to longer median progression-free

survival (PFS; 10.1 months vs. 4.4 months), including forpatients with metastases to the central nervous system(CNS; 8.5 months vs. 4.2 months). An objective responserate (ORR) of 71% was achieved with osimertinibcompared to 31% with combination platinum therapy327.Earlier phase studies confirmed the efficacy of osimertinibin this setting49,328-329. In contrast, T790M-negativepatients with acquired EGFR TKI resistance experiencedan ORR of 21% and median PFS of 2.8 months49. Asfirst-line therapy for advanced NSCLC with activating,sensitizing EGFR mutations, osimertinib compared witherlotinib or gefitinib significantly increased median PFS(18.9 vs. 10.2 months, hazard ratio of 0.46), including forpatients with CNS metastases, and showed a superiortoxicity profile330. First-line efficacy of osimertinib issupported by Phase 1 data (ORR of 77% and median PFSof 20.5 months across doses)331. A Phase 1b studycombined osimertinib with the immunotherapydurvalumab, MEK inhibitor selumetinib, or METinhibitor savolitinib and observed partial responses (PRs)for each of the combinations (9/14 PRs with durvalumab,9/23 PRs with selumetinib, 6/11 PRs with savolitinib)332.Case studies report that 2 patients with T790M-mutatedNSCLC achieved durable PRs to osimertinib rechallengeafter the adverse events induced by initial osimertinibtreatment had been resolved333-334.


Lung adenocarcinoma






SAMPLE

AAdo-do-trtrastuzumabastuzumabemtansineemtansineAssay findings association

ERBB3ERBB3P1212S

APPROAPPROVED INDICAVED INDICATIONSTIONSAdo-trastuzumab emtansine (T-DM1) is an antibody-drugconjugate that targets the protein ERBB2/HER2 on thecell surface, inhibiting HER2 signaling335-336; it alsoreleases the cytotoxic therapy DM1 into cells, leading tocell death336-337. T-DM1 is FDA approved for thetreatment of HER2-positive (HER2+), metastatic breastcancer.

GENE AGENE ASSSOCIASOCIATIONTIONERBB3/HER3 possesses a low-activity kinase domain andrequires other ERBB family members for efficientsignaling, ERBB2/HER2 in particular86-88,286;therefore, ERBB3 amplification or activating mutationsmay indicate sensitivity to therapies such as T-DM1.However, it is not known whether this therapeuticapproach would be relevant in the context of alterationsthat have not been fully characterized, as seen here.

SUPPORTING DSUPPORTING DAATTAAA patient with non-small cell lung cancer, diseaseprogression on two prior lines of chemotherapy, and anactivating ERBB2 alteration (exon 20 insertion)

experienced a rapid and durable response to T-DM1338-339. The vast majority of data on the therapeuticuse of T-DM1 has been collected in the context of breastcancer, although clinical trials investigating T-DM1 areunderway in several tumor types, primarily in HER2+cancers. A Phase 3 trial in 602 patients with HER2+breast cancer reported that those who received T-DM1showed an improved progression-free survival (PFS) anda lower rate of adverse events than patients who receivedthe physician’s choice of therapy340. A second Phase 3trial in 991 patients with HER2+ breast cancer reportedthat T-DM1 brought about significantly longer overallsurvival (OS) and PFS, as compared with lapatinib pluscapecitabine, in patients previously treated withtrastuzumab plus a taxane341-342. Two separate Phase 2trials reported robust activity for single-agent T-DM1 as atreatment for HER2+ metastatic breast cancer in patientspreviously treated with standard HER2-directed therapiesor HER2-directed therapies plus chemotherapy, withobjective response rates of 34.5% and 25.9%, respectively,and PFS of 6.9 months and 4.9 months,respectively343-344.

CaboCabozzantinibantinibAssay findings association

METMETT263M

APPROAPPROVED INDICAVED INDICATIONSTIONSCabozantinib inhibits multiple tyrosine kinases, includingMET, RET, VEGFRs, and ROS1. It is FDA approved totreat advanced renal cell carcinoma (RCC), after prior anti-angiogenic therapy, and progressive, metastatic medullarythyroid cancer (MTC).

GENE AGENE ASSSOCIASOCIATIONTIONSensitivity of MET alterations to cabozantinib issuggested by clinical responses in patients with non-smallcell lung cancer (NSCLC) harboring MET mutationsassociated with MET exon 14 skipping, with or withoutconcurrent MET amplification107,345, as well as byextensive preclinical data114-120. However, it is notknown whether this therapeutic approach would berelevant in the context of alterations that have not beenfully characterized, as seen here.

SUPPORTING DSUPPORTING DAATTAAEarly clinical data report promising activity ofcabozantinib in non-small cell lung carcinoma (NSCLC)harboring RET fusions or MET alterations. A Phase 2study of cabozantinib in RET-rearranged lungadenocarcinoma reported an objective response rate(ORR) of 28%, with 7 partial responses (PRs) in 25evaluable patients, median progression-free survival (PFS)of 6 months and overall survival of 10 months346-347. In

a retrospective analysis of patients with RET-rearrangedNSCLC treated with various RET inhibitors, of the 14patients treated with cabozantinib, 1 complete response(CR), 3 PRs, and 4 stable diseases (SDs) were reported, foran ORR of 31% and a disease control rate of 62%348.Additional studies of single-agent cabozantinib havereported 2 PRs and 1 SD in a series of 5 patients withRET-rearranged lung adenocarcinoma349, a CR in apatient with lung adenocarcinoma harboring METamplification and a mutation associated with MET exon14 skipping107, and intracranial activity of cabozantinibin a patient with MET-mutated NSCLC without co-occurring MET amplification who had previouslyprogressed on crizotinib345. In genomically unselectedpatients with metastatic NSCLC, a Phase 2 randomizeddiscontinuation trial of cabozantinib in a heavilypretreated cohort reported PRs in 10% (6/60) of patients,tumor regression in 65% (31/48) of patients, a median PFSof 4.2 months, and a safety profile similar to that of othertyrosine kinase inhibitors350. In patients with EGFRwild-type non-squamous NSCLC who have progressedafter previous treatment, patients treated withcabozantinib alone or in combination with erlotinibexperienced a longer median PFS (4.3 months and 4.7months, respectively) compared to single agent erlotinib(1.8 months)351.


Lung adenocarcinoma

IN OIN OTHER TUTHER TUMOR TMOR TYPEYPETHERTHERAPIES WITH CLINICAPIES WITH CLINICAL BENEFITAL BENEFIT





SAMPLE

CCetuximabetuximabAssay findings association


APPROAPPROVED INDICAVED INDICATIONSTIONSCetuximab is a monoclonal antibody that targets EGFR. Itis FDA approved for the treatment of head and necksquamous cell carcinoma (HNSCC) and KRAS wild-typemetastatic colorectal cancer (CRC).

GENE AGENE ASSSOCIASOCIATIONTIONEGFR activating mutations or amplification may confersensitivity to EGFR inhibitory antibodies such ascetuximab. For patients with metastatic CRC receivingcetuximab or panitumumab as mono- or combinationtherapy, increased EGFR copy number associated withimproved overall survival (hazard ratio = 0.62) in a meta-analysis, although increased survival was not seen inpopulations that received first-line treatment with EGFRantibodies352. In HNSCC, however, EGFR copy numberdid not associate with the efficacy of cetuximab pluschemotherapy353.

SUPPORTING DSUPPORTING DAATTAAIn previously untreated patients with non-small cell lungcancer (NSCLC), the FLEX study demonstrated that inNSCLC tumors with high expression of EGFR, treatmentwith cetuximab plus chemotherapy resulted in longeroverall survival compared to chemotherapy alone50.There was no clear association between cetuximab

response and EGFR mutations in the FLEX trial50. In aPhase 2 study of 31 patients with Stage 3 NSCLC, additionof cetuximab to radiotherapy and chemotherapy producedan overall response rate of 67%; EGFR gene copy numberwas not predictive of efficacy outcome354. A Phase 3study of 938 patients with progressive NSCLC afterplatinum-based therapy concluded that, in unselectedpatients, the addition of cetuximab to chemotherapy wasnot recommended in this second-line setting355.Cetuximab is also being studied as part of a therapeuticregimen for patients with EGFR mutations who developsecondary resistance to erlotinib or gefitinib. A Phase 1bstudy combining afatinib and the anti-EGFR antibodycetuximab in patients with advanced EGFR-mutant lungcancer with acquired resistance to erlotinib/gefitinibobserved an overall objective response rate of 29%, andcomparable response rates in both T790M-positive andT790M-negative tumors (32% vs. 25%)300. A Phase 1study of combination erlotinib and cetuximab treatmentin patients with NSCLC, including those with squamoustumors, inhibitor-resistant EGFR mutations, and wild-type EGFR, as well as those who had progressed on priorerlotinib treatment, reported partial responses in two of20 patients and stable disease lasting at least 6 months inthree of 20 patients356.

LapatinibLapatinibAssay findings association

EEGFRGFRERBB3ERBB3P1212S

APPROAPPROVED INDICAVED INDICATIONSTIONSLapatinib is a tyrosine kinase inhibitor that targets EGFR,ERBB2/HER2, and to a lesser degree, ERBB4. It is FDAapproved in combination with capecitabine or letrozolefor the treatment of HER2-overexpressing (HER2+)metastatic breast cancer.

GENE AGENE ASSSOCIASOCIATIONTIONActivation or amplification of EGFR may predictsensitivity to lapatinib. However, a Phase 2 study oflapatinib in non-small cell lung cancer (NSCLC) did notobserve any responses for five patients with EGFRamplification357. ERBB3/HER3 possesses a low-activitykinase domain and requires other ERBB family membersfor efficient signaling, ERBB2/HER2 inparticular86-88,286; therefore, ERBB3 amplification oractivating mutations may indicate sensitivity to therapiessuch as lapatinib86. A patient with HER2-negative breast

cancer harboring an activating ERBB3 mutation had apartial response to the combination of trastuzumab andlapatinib90.

SUPPORTING DSUPPORTING DAATTAAInvestigations into the efficacy of lapatinib have primarilybeen in the context of breast cancer. In preclinical assays,lapatinib reduced cell proliferation in vitro and reducedthe number and size of tumors in mouse xenograftmodels of EGFR- and ERBB2-amplified NSCLC cells358.A Phase 1 study of single-agent lapatinib included 9unselected patients with lung cancer and reported 1 caseof prolonged stable disease359. In a Phase 2 trial inpatients with advanced or metastatic NSCLC, lapatinibmonotherapy did not result in significant tumorreduction, but further investigation of lapatinib incombination with other therapies may be warranted357.


Lung adenocarcinoma






SAMPLE

PPanitumumabanitumumabAssay findings association


APPROAPPROVED INDICAVED INDICATIONSTIONSPanitumumab is a monoclonal antibody that targetsEGFR. It is FDA approved for the treatment of KRASwild-type metastatic colorectal cancer (CRC).

GENE AGENE ASSSOCIASOCIATIONTIONEGFR activating mutations or amplification may confersensitivity to EGFR inhibitory antibodies such aspanitumumab. For patients with metastatic CRC receivingcetuximab or panitumumab as mono- or combinationtherapy, increased EGFR copy number associated withimproved overall survival (hazard ratio = 0.62) in a meta-analysis, although increased survival was not seen in

populations that received first-line treatment with EGFRantibodies352.

SUPPORTING DSUPPORTING DAATTAAIn a Phase 2 trial of advanced non-small cell lung cancer(NSCLC), the addition of panitumumab to paclitaxel/carboplatin did not result in improved clinical benefit360,and subsequent studies investigating the addition ofpanitumumab to pemetrexed/cisplatin reported nobenefit for patients with wild-type KRAS lungadenocarcinoma361. The combination of afatinib andpanitumumab has been explored for 2 patients withEGFR T790M NSCLC, with 1 partial responsereported302.

PPerertuzumabtuzumabAssay findings association

ERBB3ERBB3P1212S

APPROAPPROVED INDICAVED INDICATIONSTIONSPertuzumab is a monoclonal antibody that interferes withthe interaction between HER2 and ERBB3. It is FDAapproved in combination with trastuzumab and docetaxelto treat patients with HER2-positive (HER2+) metastaticbreast cancer who have not received prior chemotherapyor HER2-targeted therapy. It is also approved incombination with trastuzumab and chemotherapy asneoadjuvant treatment for HER2+, locally advanced,inflammatory, or early stage breast cancer and as adjuvanttreatment for patients with HER2+ early breast cancer athigh risk of recurrence.

GENE AGENE ASSSOCIASOCIATIONTIONERBB3 amplification or activating mutations may predictsensitivity to pertuzumab. However, it is not knownwhether this therapeutic approach would be relevant inthe context of alterations that have not been fullycharacterized, as seen here.

SUPPORTING DSUPPORTING DAATTAAPertuzumab received FDA approval based on a Phase 3randomized study that demonstrated significantimprovement in progression-free survival (PFS), with atrend toward improvement in overall survival (OS), for the

combination of pertuzumab, trastuzumab, and docetaxel,as compared to treatment with trastuzumab and docetaxelalone, for patients with HER2-positive breastcancer362-363. In a Phase 1 study of pertuzumab inadvanced cancer, 2/19 patients reported partial responsesand 6/19 patients reported stable disease after two cycles,including one patient with lung cancer364. In anotherPhase 1 study in Japanese patients with solid tumors, noresponses were observed and stable disease was reportedin 1 of 7 patients with NSCLC365. In a Phase 2 study ofpertuzumab in NSCLC, no responses were observed andthe progression-free survival was 6.1 weeks366. Phase 1and 2 trials of pertuzumab in combination with erlotinibin NSCLC have reported a response rate of 20% (3/15, 2 ofthe responders had mutant EGFR)367; a reduction incirculating tumor cells was noted and correlated withreduction in tumor size368. In a Phase 2 study ofpertuzumab plus erlotinib in relapsed patients withNSCLC, PET-CT imaging showed that the primaryendpoint of response rate (RR) was met in 19.5% of allpatients (n = 41) and in 8.7% of patients with wild-typeEGFR NSCLC (n = 23); however, 68.3% (28/41) of patientsshowed treatment-related grade 3 (or higher) adverseevents369.


Lung adenocarcinoma






SAMPLE

TTrrastuzumabastuzumabAssay findings association

ERBB3ERBB3P1212S

APPROAPPROVED INDICAVED INDICATIONSTIONSTrastuzumab is a monoclonal antibody that targets theprotein ERBB2/HER2. It is FDA approved asmonotherapy and in combination with other therapies forHER2-positive (HER2+) metastatic and early breastcarcinoma and in combination with chemotherapy forHER2+ metastatic gastric or gastroesophagealadenocarcinoma.

GENE AGENE ASSSOCIASOCIATIONTIONERBB3/HER3 possesses a low-activity kinase domain andrequires other ERBB family members for efficientsignaling, ERBB2/HER2 in particular86-88,286;therefore, ERBB3 amplification or activating mutationsmay indicate sensitivity to therapies such astrastuzumab86. A patient with HER2-negative breastcancer harboring an activating ERBB3 mutation had apartial response to the combination of trastuzumab andlapatinib90. However, it is not known whether thistherapeutic approach would be relevant in the context ofalterations that have not been fully characterized, as seenhere.

SUPPORTING DSUPPORTING DAATTAAA Phase 2 clinical trial of docetaxel with trastuzumab innon-small cell lung cancer (NSCLC) reported partialresponses in 8% of patients; response did not correlatewith HER2 status as assessed byimmunohistochemistry370. Another Phase 2 study of 169patients with NSCLC reported an objective response rateof 23% (7/30 patients) in the patients treated with acombination therapy of docetaxel and trastuzumab, and32% (11/34) in patients treated with paclitaxel andtrastuzumab371. HER2 expression did not impact theresults of this study371. In a Phase 2a umbrella basketstudy, trastuzumab plus pertuzumab elicited objectiveresponses for 2/7 patients with NSCLC and ERBB2amplification or overexpression372. A patient with lungadenocarcinoma that was HER-positive by FISH andharbored an ERBB2 G776L mutation experienced apartial response on trastuzumab and paclitaxel373. In aretrospective analysis of patients with NSCLC harboringERBB2 exon 20 insertion mutations, disease control wasreported in 93% of patients (13/14) treated withtrastuzumab in combination with chemotherapy374.

TTrrastuzumab-astuzumab-dkdkststAssay findings association

ERBB3ERBB3P1212S

APPROAPPROVED INDICAVED INDICATIONSTIONSTrastuzumab-dkst is FDA approved as a biosimilartherapy to trastuzumab. Trastuzumab-dkst is amonoclonal antibody that targets the protein ERBB2/HER2, and is FDA approved as monotherapy and incombination with chemotherapy for HER2-positive(HER2+) metastatic and early breast carcinoma and incombination with chemotherapy for HER2+ metastaticgastric or gastroesophageal junction adenocarcinoma.

GENE AGENE ASSSOCIASOCIATIONTIONERBB3 possesses a low-activity kinase domain andrequires other ERBB family members for efficientsignaling, HER2 in particular86-88,286; therefore, ERBB3amplification or activating mutations may indicatesensitivity to anti-HER2 therapies such as trastuzumab-dkst86. A patient with HER2-negative breast cancer

harboring an activating ERBB3 mutation had a partialresponse to the combination of trastuzumab andlapatinib90. However, it is not known if this therapeuticapproach would be relevant in the context of alterationsthat have not been fully characterized, as seen here.

SUPPORTING DSUPPORTING DAATTAAThe Phase 3 Heritage study demonstrated comparable24-week objective response rates (69.6% vs. 64.0%) andprogression-free survival for patients with treatment-naïve HER2+ metastatic breast cancer treated with eithertrastuzumab-dkst or trastuzumab in combination withtaxane375. In both patients with HER2+ breast cancer andin healthy adults, trastuzumab-dkst demonstratedcomparable pharmacokinetic, safety, andimmunomodulation profiles to trastuzumab375-376 377.

Note: Genomic alterations detected may be associated with activity of certain FDA approved drugs, however the agents listed in this report may have little or no evidence inthe patient’s tumor type.


Lung adenocarcinoma






SAMPLE

IMPORTIMPORTANTANT Clinical trials are ordered by gene andprioritized by: age range inclusion criteria for pediatricpatients, proximity to ordering medical facility, latertrial phase, and verification of trial information withinthe last two months. While every effort is made toensure the accuracy of the information containedbelow, the information available in the public domain

is continually updated and should be investigated bythe physician or research staff. This is not acomprehensive list of all available clinical trials.Foundation Medicine displays a subset of trial optionsand ranks them in this order of descending priority:Qualification for pediatric trial → Geographicalproximity → Later trial phase. Clinical trials listed here

may have additional enrollment criteria that mayrequire medical screening to determine final eligibility.For additional information about listed clinical trials orto conduct a search for additional trials, please seeclinicaltrials.gov. Or, visithttps://www.foundationmedicine.com/genomic-testing#support-services.

GENEGENE

EEGFRGFRALALTERATERATIONTION

amplification, exon 19 deletion(T751_I759>S)

RARATIONALETIONALEEGFR amplification or activating mutations maypredict sensitivity to EGFR-targeted therapies.Several strategies to circumvent resistance areunder investigation, including irreversible EGFRtyrosine kinase inhibitors and the use of HSP90inhibitors. Examples of clinical trials that may beappropriate for this patient are listed below. Thesetrials were identified through a search of the trial

website clinicaltrials.gov using keyword termssuch as "EGFR", "cetuximab", "panitumumab","erlotinib", "gefitinib", "lapatinib", "afatinib","osimertinib", "BIBW 2992", "CO-1686","AZD9291", "PF-00299804", "HSP90", "reolysin","NSCLC", "lung", "solid tumor", and/or "advancedcancer".

NCT0NCT021921932823282 PHAPHASE 3SE 3

Randomized Double Blind Placebo Controlled Study of Erlotinib or Placebo in Patients WithCompletely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer(NSCLC)

TTARGETARGETSS

EEGFRGFR

LLOCAOCATIONS:TIONS: Kentucky, Tennessee, New Jersey, Alaska, Delaware, North Dakota, Montana, Ohio, Rhode Island, Maine, New Hampshire, Arizona, Wyoming,Hawaii, Georgia, South Carolina, West Virginia, Connecticut, Vermont, California, Michigan, Alabama, Nebraska, Texas, Arkansas, Nevada, Idaho,Washington, Iowa, Mississippi, Missouri, Wisconsin, Colorado, Louisiana, Virginia, South Dakota, New York, Oklahoma, Utah, Massachusetts, Florida,Maryland, Oregon, Indiana, Kansas, District of Columbia, Illinois, Minnesota, North Carolina, Pennsylvania, New Mexico


A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacyand Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor MutationPositive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With orWithout Adjuvant Chemotherapy (ADAURA).

TTARGETARGETSS

EEGFRGFR

LLOCAOCATIONS:TIONS: Maryland, Guangzhou (China), Rio Grande do Sul (Brazil), Beer-Sheva (Israel), Hoofddorp (Netherlands), Vinnytsia (Ukraine), Nanjing (China),Taichung (Taiwan), Hamburg (Germany), Poznan (Poland), Kurralta Park (Australia), Iasi (Romania), Beijing (China), Saint-Petersburg (Russian Federation),Ankara (Turkey), Virginia, Milano (Italy), Seoul (Korea, Republic of), Muang (Thailand), Dnipropetrovsk (Ukraine), Fortaleza (Brazil), Zaporizhzhya(Ukraine), Limoges (France), Brussels (Belgium), Gent (Belgium), St. Petersburg (Russian Federation), Halle (Germany), Budapest (Hungary), New Jersey,Bron (France), Lugo (Spain), Changchun (China), Saint Petersburg (Russian Federation), Lyon (France), Curitiba (Brazil), Hawaii, Hangzhou (China),Zaragoza (Spain), Camperdown (Australia), Bergamo (Italy), Yonago-shi (Japan), Großhansdorf (Germany), Chiayi (Taiwan), Roma (Italy), Tainan (Taiwan),Łódź (Poland), Paris (France), Illinois, Otwock (Poland), Colorado, Immenhausen (Germany), Bedford Park (Australia), São José do Rio Preto (Brazil),Aachen (Germany), Arnhem (Netherlands), Washington, Kashiwa-shi (Japan), Taipei (Taiwan), Parma (Italy), Racibórz (Poland), San Sebastian (Spain),Shinjuku-ku (Japan), Liou Ying Township (Taiwan), Ho Chi Minh (Vietnam), Sagamihara-shi (Japan), Bunkyo-ku (Japan), Málaga (Spain), Sunto-gun (Japan),Kanazawa (Japan), Kogarah (Australia), Timisoara (Romania), Sankt-Peterburg (Russian Federation), Ube-shi (Japan), Suwon-si (Korea, Republic of), Suwon(Korea, Republic of), Yangzhou (China), California, Livorno (Italy), Changhua (Taiwan), Xi'an (China), Székesfehérvár (Hungary), Sakai-shi (Japan),Osakasayama-shi (Japan), Khonkaen (Thailand), Izmir (Turkey), Meldola (Italy), Urumqi (China), Sendai-shi (Japan), Matsuyama-shi (Japan), Yokohama-shi (Japan), Sasebo-shi (Japan), Bruxelles (Belgium), Phitsanulok (Thailand), Lucca (Italy), Gauting (Germany), Homburg (Germany), Ryazan (RussianFederation), Gerlingen (Germany), Suzhou (China), Linköping (Sweden), Lübeck (Germany), Arkhangelsk (Russian Federation), Chom Thon (Thailand),Tennessee, Hanoi (Vietnam), São Paulo (Brazil), Hirakata-shi (Japan), Hiroshima-shi (Japan), Focsani (Romania), Bangkok (Thailand), Tianjin (China),Coswig (Germany), Salvador (Brazil), Ottignies (Belgium), Urumchi (China), Brussels (Anderlecht) (Belgium), Torokbalint (Hungary), Bologna (Italy),Pyatigorsk (Russian Federation), Rhode Island, Majadahonda (Spain), Uzhgorod (Ukraine), Valencia (Spain), Porto Alegre (Brazil), Florida, Hong Kong (HongKong), Georgia, Cheongju-si (Korea, Republic of), Tel Hashomer (Israel), Las Palmas de Gran Canaria (Spain), A Coruña (Spain), Köln (Germany), Eindhoven(Netherlands), Kassel (Germany), Shanghai (China), Santa Catarina (Brazil), Madrid (Spain), Florianópolis (Brazil), Cachoeira De Itapemirim (Brazil), Lillecedex (France), Bursa (Turkey), Bari (Italy), Nagoya-shi (Japan), Palermo (Italy), Heidelberg (Australia), Lviv (Ukraine), Songkla (Thailand), Padova (Italy),Haifa (Israel), Kunming (China), Istanbul (Turkey), Zwolle (Netherlands), Barcelona (Spain), Kortrijk (Belgium), Barretos (Brazil), Zhengzhou (China),Moscow (Russian Federation), Trier (Germany), Bucuresti (Romania), Itajai (Brazil), Craiova (Romania), Berlin (Germany), Dalian (China), Oslo (Norway),Baudour (Belgium), Novara (Italy), Tel Aviv (Israel), Connecticut, Kfar Saba (Israel), Cremona (Italy), Petah Tikva (Israel), Nanning (China), Kitakyushu-shi(Japan), Elche (Spain), Woolloongabba (Australia), Kazan (Russian Federation), Darlinghurst (Australia), Xiamen (China), Sumy (Ukraine), Kobe-shi(Japan), Bucharest (Romania), Frankston (Australia)


Lung adenocarcinoma

CLINICCLINICAL TRIALSAL TRIALS





SAMPLE

https://www.foundationmedicine.com/genomic-testing#support-services

https://www.foundationmedicine.com/genomic-testing#support-services


A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab orPlacebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell LungCancer

TTARGETARGETSS

EEGFR, VEGFR, VEGFR2GFR2

LLOCAOCATIONS:TIONS: Pordenone (Italy), Jinju (Korea, Republic of), Pok Fu Lam (Hong Kong), Texas, Chemnitz (Germany), Kaohsiung City (Taiwan), Poitiers (France),Hyogo (Japan), Dongjak-gu (Korea, Republic of), Taichung (Taiwan), Osaka (Japan), Cluj-Napoca (Romania), Pennsylvania, Kobe (Japan), Fukuoka (Japan),Grenoble (France), Gerlingen (Germany), Pamplona (Spain), Málaga (Spain), Okayama (Japan), Suwon (Korea, Republic of), Bucuresti (Romania), Torino(Italy), Milano (Italy), Montpellier (France), Taipei (Taiwan), Taoyuan (Taiwan), Hong Kong (Hong Kong), Akashi (Japan), Lille (France), New York, Berlin(Germany), Merseyside (United Kingdom), Wolverhampton (United Kingdom), Nagoya (Japan), Massachusetts, Nottingham (United Kingdom), Miyagi(Japan), Barcelona (Spain), Ravenna (Italy), Himeji (Japan), Hirakata (Japan), Paris (France), Ube (Japan), Hawaii, North Carolina, Edmonton (Canada),California, Ulm (Germany), Matsuyama (Japan), Kyoto (Japan), Hwasun (Korea, Republic of), Yau Ma Tei (Hong Kong), Bron (France), Kurume (Japan),London (United Kingdom), Nagasaki (Japan), Wakayama (Japan), Kansas, London (Canada), Lai Chi Kok (Hong Kong), Tokyo (Japan), Seowon-gu (Korea,Republic of), Kashiwa (Japan), Saitama (Japan), Preston (United Kingdom), Kishiwada (Japan), Florida, Großhansdorf (Germany), Sevilla (Spain), Otopeni(Romania), Valencia (Spain), Habikino (Japan), Bunkyo-Ku (Japan), Yokohama (Japan), Chelsea (United Kingdom), Palma de Mallorca (Spain), Tainan(Taiwan), Bologna (Italy), Osakasayama (Japan), Kanazawa (Japan), Niigata (Japan), Seoul (Korea, Republic of), Asahikawa (Japan), Athens (Greece),Seongnam-Si (Korea, Republic of), Shizuoka (Japan), Patras (Greece), Padova (Italy), Oregon, Sakai (Japan), Köln (Germany), Chiba (Japan), Ulsan-si(Korea, Republic of), Madrid (Spain), Heidelberg (Germany)

NCT0NCT022438438772222 PHAPHASE 2 / PHASE 2 / PHASE 3SE 3

A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-NaivePatients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

TTARGETARGETSS

EEGFR, ERBB2, ERBB4GFR, ERBB2, ERBB4

LLOCAOCATIONS:TIONS: Vermont, Kentucky, New York, Mississippi, Idaho, Iowa, New Jersey, Massachusetts, Florida, Indiana, Wisconsin, Oregon, North Dakota,Montana, Ohio, Tennessee, Maine, South Dakota, New Hampshire, Oklahoma, West Virginia, Hawaii, Pennsylvania, Colorado, South Carolina, Wyoming,California, Michigan, Kansas, Nebraska, Illinois, Missouri, Minnesota, North Carolina, Georgia, Connecticut, Texas, Washington, New Mexico, Arkansas


A Randomized Phase II Study of Individualized Combined Modality Therapy for Stage III Non-SmallCell Lung Cancer (NSCLC)

TTARGETARGETSS

METMET, E, EGFR, ALK, TGFR, ALK, TOP2, ROP2, ROOS1, AXL,S1, AXL,TRKTRKC, TRKAC, TRKA

LLOCAOCATIONS:TIONS: Connecticut, Idaho, Iowa, New Jersey, Massachusetts, Indiana, Oregon, Missouri, New Hampshire, Maine, Illinois, Colorado, Maryland,Oklahoma, Arizona, Wisconsin, South Carolina, Nebraska, Florida, Minnesota, Texas, Pennsylvania, California, West Virginia, Michigan, Ohio, Delaware,Georgia, North Carolina, New York


EValuation of Erlotinib as a Neoadjuvant Therapy in Stage III NSCLC Patients With EGFR Mutations(EVENT Trial)

TTARGETARGETSS

EEGFRGFR

LLOCAOCATIONS:TIONS: New York


A Phase I/II, Multicenter, Open-label Study of EGFRmut-TKI EGF816, Administered Orally in AdultPatients With EGFRmut Solid Malignancies

TTARGETARGETSS

EEGFRGFR

LLOCAOCATIONS:TIONS: Madrid (Spain), Taipei (Taiwan), Nagoya (Japan), Fukuoka (Japan), Massachusetts, Singapore (Singapore), Seoul (Korea, Republic of), NewYork, Berlin (Germany), Koeln (Germany), Milano (Italy), Amsterdam (Netherlands), Barcelona (Spain), Toronto (Canada)


A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2Inhibitor AP32788 in Non-Small Cell Lung Cancer

TTARGETARGETSS

EEGFR, ERBB2GFR, ERBB2

LLOCAOCATIONS:TIONS: New York, California, Tennessee, Massachusetts, Colorado, Virginia


Lung adenocarcinoma






SAMPLE


A Master Protocol of Phase 1/2 Studies of Nivolumab in Advanced NSCLC Using Nivolumab asMaintenance After Induction Chemotherapy or as First-line Treatment Alone or in Combination WithStandard of Care Therapies (CheckMate 370: CHECKpoint Pathway and nivoluMAb Clinical TrialEvaluation 370)

TTARGETARGETSS

EEGFR, PD-GFR, PD-11

LLOCAOCATIONS:TIONS: Mississippi, Nebraska, North Carolina, Ohio, Colorado, California, Tennessee, Oklahoma, Pennsylvania, New Mexico, Indiana, Alabama,Virginia, Kansas, Illinois, North Dakota, Minnesota, Oregon, New York, Michigan, Missouri, Louisiana, South Carolina, Maine, Texas, Nevada, Kentucky,Georgia, New Jersey, Washington, West Virginia, Montana, Arizona, Connecticut, South Dakota, Maryland, Florida


Phase 1/2 Open-Label Study Of PF-06747775 (Epidermal Growth Factor Receptor T790m Inhibitor) InPatients With Advanced Epidermal Growth Factor Receptor Mutant (Del 19 Or L858R ± T790M) Non-Small Cell Lung Cancer

TTARGETARGETSS

EEGFRGFR

LLOCAOCATIONS:TIONS: Seoul (Korea, Republic of), Washington, California, Connecticut, Pennsylvania


Lung adenocarcinoma






SAMPLE

GENEGENE

ERBB3ERBB3ALALTERATERATIONTION

P1212S

RARATIONALETIONALEERBB3 amplification or activating mutations maybe associated with response to therapies targetingERBB3. Additionally, the oncogenic effects ofERBB3 mutations have been shown to depend onERBB2/HER2, and tumors with ERBB3oncogenic mutations may therefore be sensitive totherapies that target ERBB2/HER2. However,because this mutation has not been functionallycharacterized, it is not known whether theseapproaches are beneficial here. Examples of

clinical trials that may be appropriate for thispatient are listed below. These trials wereidentified through a search of the trial websiteclinicaltrials.gov using keyword terms such as"ERBB3", "MM-121", "U3-1287", "AV-203","afatinib", "pertuzumab", "lapatinib","trastuzumab", "ado-trastuzumab emtansine","lung", "NSCLC", "solid tumor", and/or "advancedcancer".


A Phase 1b Open-label Three-arm Multi-center Study To Assess The Safety And Tolerability OfPf-05212384 (pi3k/Mtor Inhibitor) In Combination With Other Anti-tumor Agents

TTARGETARGETSS

EEGFR, mTGFR, mTORORC1, ERBB2, PI3KC1, ERBB2, PI3K--ggamma, mTamma, mTORORC2, PI3KC2, PI3K-alpha,-alpha,ERBB4ERBB4

LLOCAOCATIONS:TIONS: London (United Kingdom), Massachusetts, South Carolina, California, Milan (Italy), Vancouver (Canada), Madrid (Spain), Pennsylvania,Toronto (Canada), Barcelona (Spain), Michigan, Roma (Italy)


Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer,Small Cell Lung Cancer, and Thymic Malignancies

TTARGETARGETSS

AKAKTTs, Es, EGFR, RETGFR, RET, ERBB2, MEK,, ERBB2, MEK,FLFLT3, VET3, VEGFRs, CSF1R, PDGFRs, KITGFRs, CSF1R, PDGFRs, KIT

LLOCAOCATIONS:TIONS: Maryland


Molecular Basket Trial In Multiple Malignancies With Common Target Pathway Aberrancies TTARGETARGETSS


LLOCAOCATIONS:TIONS: Toronto (Canada)


Phase I/IB Multi-center Study of Irreversible EGFR/HER2 Tyrosine Kinase Inhibitor Afatinib (BIBW2992) in Combination With Capecitabine for Advanced Solid Tumors and Pancretico-Biliary Cancers

TTARGETARGETSS


LLOCAOCATIONS:TIONS: Indiana, Washington


A Phase I/II Study of MCLA-128, a Full Length IgG1 Bispecific Antibody Targeting HER2 and HER3, inPatients With Solid Tumors

TTARGETARGETSS

ERBB2, ERBB3ERBB2, ERBB3

LLOCAOCATIONS:TIONS: Milan (Italy), Madrid (Spain), Paris (France), Amsterdam (Netherlands), Barcelona (Spain)


Lung adenocarcinoma






SAMPLE

GENEGENE

METMETALALTERATERATIONTION

T263M

RARATIONALETIONALEActivation of MET may lead to increased METexpression and activation and may thereforeconfer sensitivity to MET inhibitors. However, itis not known whether these therapeuticapproaches would be relevant in the context ofalterations that have not been fully characterized,as seen here. Examples of clinical trials that may

be appropriate for this patient are listed below.These trials were identified through a search ofthe trial website clinicaltrials.gov using keywordterms such as "c-MET", "crizotinib", "cabozantinib","INC280", "MGCD265", "NSCLC", and/or "solidtumor".


A Phase II Study of Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell LungCancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity

TTARGETARGETSS

METMET, R, ROOS1, RETS1, RET, VE, VEGFRsGFRs

LLOCAOCATIONS:TIONS: New York, New Jersey


A Phase II, Multicenter Study of Oral cMET Inhibitor INC280 in Adult Patients With EGFR Wild-type(wt), Advanced Non-small Cell Lung Cancer (NSCLC)

TTARGETARGETSS

METMET

LLOCAOCATIONS:TIONS: Arkansas, California, Connecticut, Florida, Georgia, Illinois, Iowa, Massachusetts, Michigan, Minnesota, Nebraska, New Hampshire, New York,Oregon, Pennsylvania, South Carolina, Tennessee, Texas, Utah, Virginia, multiple ex-US locations


A Parallel Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab inAdvanced or Metastatic Non-Small Cell Lung Cancer

TTARGETARGETSS

METMET, HD, HDAAC, PDGFRA, RETC, PDGFRA, RET, PD-, PD-1,1,KITKIT, DDR2, VE, DDR2, VEGFRs, FLGFRs, FLT3, AXL,T3, AXL,TRKB, TRKATRKB, TRKA

LLOCAOCATIONS:TIONS: Virginia, Tennessee, Wisconsin, Pennsylvania, Alabama, Ohio, Michigan, California


Targeted Agent and Profiling Utilization Registry (TAPUR) Study TTARGETARGETSS

ABL, CDK4, PABL, CDK4, PARPARP, E, EGFR, DDR2,GFR, DDR2,VEVEGFRs, PDGFRs, RGFRs, PDGFRs, ROOS1, CSF1R,S1, CSF1R,ERBB2, PD-ERBB2, PD-1, ERBB3, MEK, RAF1,1, ERBB3, MEK, RAF1,KITKIT, SMO, SMO, AXL, TRK, AXL, TRKC, mTC, mTOR,OR,TRKA, METTRKA, MET, ALK, BRAF, ALK, BRAF, RET, RET, SR, SRC,C,FLFLT3, CDK6T3, CDK6

LLOCAOCATIONS:TIONS: North Dakota, Pennsylvania, Washington, Illinois, Georgia, Arizona, Utah, North Carolina, Oklahoma, South Dakota, Michigan, Oregon,Nebraska


A Phase 1b/2, Open Label, Dose Finding Study To Evaluate Safety, Efficacy, Pharmacokinetics AndPharmacodynamics Of Avelumab (msb0010718c) In Combination With Either Crizotinib Or Pf06463922 In Patients With Advanced Or Metastatic Non Small Cell Lung Cancer Javelin Lung 101

TTARGETARGETSS

METMET, ALK, PD-L1, R, ALK, PD-L1, ROOS1, AXL,S1, AXL,TRKTRKC, TRKAC, TRKA

LLOCAOCATIONS:TIONS: Badalona (Spain), Camperdown (Australia), Barcelona (Spain), Georgia, Tennessee, Goyang-Si (Korea, Republic of), Goyang-si (Korea,Republic of), Melbourne (Australia), Massachusetts, Parkville (Australia), Fukuoka (Japan), Seoul (Korea, Republic of), Chermside (Australia)


Lung adenocarcinoma






SAMPLE


Phase 1 Safety, Pharmacokinetic And Pharmacodynamic Study Of Pf-02341066, A C-met/HgfrSelective Tyrosine Kinase Inhibitor, Administered Orally To Patients With Advanced Cancer

TTARGETARGETSS

METMET, ALK, R, ALK, ROOS1, AXL, TRKS1, AXL, TRKC, TRKAC, TRKA

LLOCAOCATIONS:TIONS: New York, Michigan, California, Colorado, Pennsylvania, Akashi (Japan), Massachusetts, Melbourne (Australia), North Carolina, Ohio, Seoul(Korea, Republic of), Vermont, Sapporo (Japan), Osakasayama (Japan)


Open-Label Dose-Escalation Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamicsof Daily Oral MGCD265 Administered Without Interruption to Subjects With Advanced Malignancies

TTARGETARGETSS

METMET, AXL, AXL

LLOCAOCATIONS:TIONS: Texas, North Carolina, Pennsylvania, New York, Gyeonggi-do (Korea, Republic of), Edmonton (Canada), Montreal (Canada), Utah, Illinois,Massachusetts, Missouri, Vancouver (Canada), Seoul (Korea, Republic of), Washington, California


A Phase 1/1b Study of MGCD516 in Patients With Advanced Solid Tumor Malignancies TTARGETARGETSS

METMET, PDGFRA, RET, PDGFRA, RET, KIT, KIT, DDR2,, DDR2,VEVEGFRs, FLGFRs, FLT3, AXL, TRKB, TRKAT3, AXL, TRKB, TRKA

LLOCAOCATIONS:TIONS: Texas, Nebraska, Tennessee, Wisconsin, Florida, Pennsylvania, Seoul (Korea, Republic of), Alabama, Virginia, South Carolina, Illinois, Utah,California, Missouri, New York, Washington, Massachusetts, Michigan, New Mexico


A Multicenter, Phase 1/1b, Open-Label, Dose-Escalation Study of ABBV-399, an Antibody DrugConjugate, in Subjects With Advanced Solid Tumors

TTARGETARGETSS

METMET, E, EGFR, VEGFR, VEGFGFA, PD-A, PD-11

LLOCAOCATIONS:TIONS: Villejuif, Cedex (France), Colorado, Illinois, Massachusetts, Tennessee, Michigan, Missouri, Marseille (France), California, North Carolina,Virginia, Texas


A Single-Arm Phase II Clinical Trial of Cabozantinib (XL184) in Patients With Previously Treated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases With and Without C Met Amplification

TTARGETARGETSS

METMET, R, ROOS1, RETS1, RET, VE, VEGFRsGFRs

LLOCAOCATIONS:TIONS: Pennsylvania


Lung adenocarcinoma






SAMPLE

NONOTETE One or more variants of unknown significance (VUS) were detected in this patient's tumor. These variants may not have been adequately characterized inthe scientific literature at the time this report was issued, and/or the genomic context of these alterations makes their significance unclear. We choose toinclude them here in the event that they become clinically meaningful in the future.

ATRA2165T

EPHB1I332V

IDH1I102T

IRF2E232G

IRF4amplification

NOTCH3V508L

ROS1S1463N

SDHAamplification

TEKloss


Lung adenocarcinoma

VVariants of Unknoariants of Unknown Significancwn SignificanceeAPPENDIXAPPENDIX



APPENDIX - PAGE 1 of 13

SAMPLE

INTENDED USEINTENDED USEFoundationOne CDx™ (F1CDx) is a nextgeneration sequencing based in vitro diagnosticdevice for detection of substitutions, insertion anddeletion alterations (indels), and copy numberalterations (CNAs) in 324 genes and select generearrangements, as well as genomic signaturesincluding microsatellite instability (MSI) and tumormutational burden (TMB) using DNA isolated fromformalin-fixed paraffin embedded (FFPE) tumortissue specimens. The test is intended as acompanion diagnostic to identify patients who maybenefit from treatment with the targeted therapieslisted in Table 1 in accordance with the approvedtherapeutic product labeling. Additionally, F1CDx isintended to provide tumor mutation profiling to beused by qualified health care professionals inaccordance with professional guidelines inoncology for patients with solid malignantneoplasms. The F1CDx assay is a single-site assayperformed at Foundation Medicine, Inc.

INDICATION GENOMIC FINDINGS THERAPY

EGFR exon 19 deletions and EGFR exon 21L858R alterations

Gilotrif® (Afatinib),Iressa® (Gefitinib), orTarceva® (Erlotinib)

EGFR exon 20 T790M alterations Tagrisso® (Osimertinib)

ALK rearrangementsAlecensa® (Alectinib),Xalkori® (Crizotinib), orZykadia® (Ceritinib)

Non-small celllung cancer(NSCLC)

BRAF V600E Tafinlar® (Dabrafenib) in combination withMekinist® (Trametinib)

BRAF V600E Tafinlar® (Dabrafenib) orZelboraf® (Vemurafenib)

Melanoma

BRAF V600E or V600KMekinist® (Trametinib) orCotellic® (Cobimetinib), in combination withZelboraf® (Vemurafenib)

Breast cancer ERBB2 (HER2) amplificationHerceptin® (Trastuzumab),Kadcyla® (Ado-trastuzumab emtansine), orPerjeta® (Pertuzumab)

KRAS wild-type (absence of mutations incodons 12 and 13) Erbitux® (Cetuximab)

Colorectal cancer KRAS wild-type (absence of mutations inexons 2, 3, and 4) and NRAS wild type(absence of mutations in exons 2, 3, and 4)

Vectibix® (Panitumumab)

Ovarian cancer BRCA1/2 alterations Rubraca® (Rucaparib)

TTABLE 1ABLE 1

TThe median ehe median exxon con coovvereragage fe for this sample is 86or this sample is 869x9x


Lung adenocarcinoma

About FAbout FoundationOne CDoundationOne CDXX™™APPENDIXAPPENDIX




SAMPLE

TESTEST PRINCIPLET PRINCIPLEFoundationOne CDx will be performedexclusively as a laboratory service using DNAextracted from formalin-fixed, paraffin-embedded(FFPE) tumor samples. The proposed assay willemploy a single DNA extraction method fromroutine FFPE biopsy or surgical resectionspecimens, 50-1000 ng of which will undergowhole-genome shotgun library construction andhybridization-based capture of all coding exonsfrom 309 cancer-related genes, one promoterregion, one non-coding (ncRNA), and selectintronic regions from 34 commonly rearrangedgenes, 21 of which also include the coding exons.The assay therefore includes detection ofalterations in a total of 324 genes. Using theIllumina® HiSeq 4000 platform, hybridcapture–selected libraries will be sequenced tohigh uniform depth (targeting >500X mediancoverage with >99% of exons at coverage >100X).Sequence data will be processed using acustomized analysis pipeline designed toaccurately detect all classes of genomic alterations,including base substitutions, indels, focal copynumber amplifications, homozygous genedeletions, and selected genomic rearrangements(e.g., gene fusions). Additionally, genomicsignatures including microsatellite instability(MS) and tumor mutational burden (TMB) will bereported.

PERFORMANCE CHARAPERFORMANCE CHARACTERISCTERISTICSTICSPlease refer to product label:foundationmedicine.com/f1cdx

LIMITLIMITAATIONSTIONS1.1. For in vitro diagnostic use.2.2. For prescription use only. This test must be

ordered by a qualified medical professional inaccordance with clinical laboratoryregulations.

33.. Genomic findings other than those listed inTable 1 of the intended use are notprescriptive or conclusive for labeled use ofany specific therapeutic product.

4.4. A negative result does not rule out thepresence of a mutation below the limits ofdetection of the assay.

5.5. Samples with <25% tumor may havedecreased sensitivity for the detection ofCNAs including ERBB2.

6.6. Clinical performance of Tagrisso®(osimertinib) in patients with an EGFR exon20 T790M mutation detected with an allelefraction <5% is ongoing and has not beenestablished.

77.. Concordance with other validated methodsfor CNA (with the exception of ERBB2) andgene rearrangement (with the exception ofALK) detection has not been demonstratedand will be provided in the post-marketsetting. Confirmatory testing using aclinically validated assay should be performedfor all CNAs and rearrangements notassociated with CDx claims noted in Table 1of the Intended Use, but used for clinicaldecision making.

8.8. The MSI-H/MSS designation by FMI F1CDxtest is based on genome wide analysis of 95microsatellite loci and not based on the 5 or 7MSI loci described in current clinical practiceguidelines. Refer to the Summary of Safety ofEffectiveness Data (SSED) for additionaldetails on methodology. The threshold forMSI-H/MSS was determined by analyticalconcordance to comparator assays (IHC andPCR) using uterine, cecum and colorectalcancer FFPE tissue. The clinical validity of thequalitative MSI designation has not beenestablished.

99.. TMB by F1CDx is defined based on countingthe total number of all synonymous and non-synonymous variants present at 5% allelefrequency or greater (after filtering) andreported as mutations per megabase (mut/Mb) unit. The clinical validity of TMB definedby this panel has not been established.

1010..Decisions on patient care and treatment mustbe based on the independent medicaljudgment of the treating physician, takinginto consideration all applicable informationconcerning the patient’s condition, such aspatient and family history, physicalexaminations, information from otherdiagnostic tests, and patient preferences, inaccordance with the standard of care in agiven community.

11.11. The test is intended to be performed onspecific serial number-controlled instrumentsby Foundation Medicine, Inc.


Lung adenocarcinoma

About FAbout FoundationOne CDoundationOne CDXX™™APPENDIXAPPENDIX




SAMPLE

FoundationOne CDx™ is designed to include all genes known to be somatically altered in human solid tumors that are validated targets for therapy, eitherapproved or in clinical trials, and/or that are unambiguous drivers of oncogenesis based on current knowledge. The current assay interrogates 324 genes aswell as introns of 28 genes involved in rearrangements. The assay will be updated periodically to reflect new knowledge about cancer biology.

DNA GENE LISDNA GENE LISTT: ENTIRE C: ENTIRE CODING SEQUENCE FOR THE DETECTION OF BAODING SEQUENCE FOR THE DETECTION OF BASE SUBSSE SUBSTITUTIONS, INSERTION/DELETIONS, AND CTITUTIONS, INSERTION/DELETIONS, AND COPOPY NUMBERY NUMBERALALTERATERATIONSTIONSABL1 ACVR1B AKT1 AKT2 AKT3 ALK ALOX12B AMER1 (FAM123B) APCAR ARAF ARFRP1 ARID1A ASXL1 ATM ATR ATRX AURKAAURKB AXIN1 AXL BAP1 BARD1 BCL2 BCL2L1 BCL2L2 BCL6BCOR BCORL1 BRAF BRCA1 BRCA2 BRD4 BRIP1 BTG1 BTG2BTK C11orf30 (EMSY) C17orf39 (GID4) CALR CARD11 CASP8 CBFB CBL CCND1CCND2 CCND3 CCNE1 CD22 CD274 (PD-L1) CD70 CD79A CD79B CDC73CDH1 CDK12 CDK4 CDK6 CDK8 CDKN1A CDKN1B CDKN2A CDKN2BCDKN2C CEBPA CHEK1 CHEK2 CIC CREBBP CRKL CSF1R CSF3RCTCF CTNNA1 CTNNB1 CUL3 CUL4A CXCR4 CYP17A1 DAXX DDR1DDR2 DIS3 DNMT3A DOT1L EED EGFR EP300 EPHA3 EPHB1EPHB4 ERBB2 ERBB3 ERBB4 ERCC4 ERG ERRFI1 ESR1 EZH2FAM46C FANCA FANCC FANCG FANCL FAS FBXW7 FGF10 FGF12FGF14 FGF19 FGF23 FGF3 FGF4 FGF6 FGFR1 FGFR2 FGFR3FGFR4 FH FLCN FLT1 FLT3 FOXL2 FUBP1 GABRA6 GATA3GATA4 GATA6 GNA11 GNA13 GNAQ GNAS GRM3 GSK3B H3F3AHDAC1 HGF HNF1A HRAS HSD3B1 ID3 IDH1 IDH2 IGF1RIKBKE IKZF1 INPP4B IRF2 IRF4 IRS2 JAK1 JAK2 JAK3JUN KDM5A KDM5C KDM6A KDR KEAP1 KEL KIT KLHL6KMT2A (MLL) KMT2D (MLL2) KRAS LTK LYN MAF MAP2K1 (MEK1) MAP2K2 (MEK2) MAP2K4MAP3K1 MAP3K13 MAPK1 MCL1 MDM2 MDM4 MED12 MEF2B MEN1MERTK MET MITF MKNK1 MLH1 MPL MRE11A MSH2 MSH3MSH6 MST1R MTAP MTOR MUTYH MYC MYCL (MYCL1) MYCN MYD88NBN NF1 NF2 NFE2L2 NFKBIA NKX2-1 NOTCH1 NOTCH2 NOTCH3NPM1 NRAS NT5C2 NTRK1 NTRK2 NTRK3 P2RY8 PALB2 PARK2PARP1 PARP2 PARP3 PAX5 PBRM1 PDCD1 (PD-1) PDCD1LG2 (PD-L2) PDGFRA PDGFRBPDK1 PIK3C2B PIK3C2G PIK3CA PIK3CB PIK3R1 PIM1 PMS2 POLD1POLE PPARG PPP2R1A PPP2R2A PRDM1 PRKAR1A PRKCI PTCH1 PTENPTPN11 PTPRO QKI RAC1 RAD21 RAD51 RAD51B RAD51C RAD51DRAD52 RAD54L RAF1 RARA RB1 RBM10 REL RET RICTORRNF43 ROS1 RPTOR SDHA SDHB SDHC SDHD SETD2 SF3B1SGK1 SMAD2 SMAD4 SMARCA4 SMARCB1 SMO SNCAIP SOCS1 SOX2SOX9 SPEN SPOP SRC STAG2 STAT3 STK11 SUFU SYKTBX3 TEK TET2 TGFBR2 TIPARP TNFAIP3 TNFRSF14 TP53 TSC1TSC2 TYRO3 U2AF1 VEGFA VHL WHSC1 WHSC1L1 WT1 XPO1XRCC2 ZNF217 ZNF703

DNA GENE LISDNA GENE LISTT: FOR THE DETECTION OF SELECT REARRANGEMENT: FOR THE DETECTION OF SELECT REARRANGEMENTSSALK BCL2 BCR BRAF BRCA1 BRCA2 CD74 EGFR ETV4ETV5 ETV6 EWSR1 EZR FGFR1 FGFR2 FGFR3 KIT KMT2A (MLL)MSH2 MYB MYC NOTCH2 NTRK1 NTRK2 NUTM1 PDGFRA RAF1RARA RET ROS1 RSPO2 SDC4 SLC34A2 TERC* TERT** TMPRSS2*TERC IS A NCRNA**THE PROMOTER REGION OF TERT INTERROGATED

ADDITIONAL AADDITIONAL ASSSSAAYYS: FOR THE DETECTION OF SELECT CANCER BIOMARKERSS: FOR THE DETECTION OF SELECT CANCER BIOMARKERSMicrosatellite Status (MS)Tumor Mutation Burden (TMB)


Lung adenocarcinoma

Genes asGenes assasayyed in Fed in FoundationOne CDoundationOne CDxxAPPENDIXAPPENDIX




SAMPLE

QUQUALIFIED ALALIFIED ALTERATERATION CALLSTION CALLS(EQUIV(EQUIVOCAL AND SUBCLOCAL AND SUBCLONAL)ONAL)An alteration denoted as “amplification–equivocal” implies that the FoundationOneCDx™ assay data provide some, but notunambiguous, evidence that the copy number ofa gene exceeds the threshold for identifying copynumber amplification. The threshold used inFoundationOne CDx™ for identifying a copynumber amplification is four (4) for ERBB2 andsix (6) for all other genes. Conversely, analteration denoted as “loss – equivocal” impliesthat the FoundationOne CDx™ assay dataprovide some, but not unambiguous, evidence forhomozygous deletion of the gene in question. Analteration denoted as “subclonal” is one that theFoundationOne CDx™ analytical methodologyhas identified as being present in <10% of theassayed tumor DNA.

PROFESPROFESSIONAL SERSIONAL SERVICES FINDINGSVICES FINDINGSIncorporates analyses of peer-reviewed studiesand other publicly available informationidentified by Foundation Medicine; theseanalyses and information may includeassociations between a molecular alteration (orlack of alteration) and one or more drugs withpotential clinical benefit (or potential lack ofclinical benefit), including drug candidates thatare being studied in clinical research. NOTE: Afinding of biomarker alteration does notnecessarily indicate pharmacologic effectiveness(or lack thereof) of any drug or treatmentregimen; a finding of no biomarker alterationdoes not necessarily indicate lack ofpharmacologic effectiveness (or effectiveness) ofany drug or treatment regimen.

RANKING OF ALRANKING OF ALTERATERATIONS ANDTIONS ANDDRUGSDRUGSBiomarker FindingsAppear at the top of the report, but are notranked higher than Genomic Findings.

Genomic FindingsTherapies with Clinical Benefit In Patient’sTumor Type → Therapies with Clinical Benefit inOther Tumor Type → Clinical Trial Options → NoKnown Options (if multiple findings exist withinany of these categories, the results are listedalphabetically by gene name).

TherapiesSensitizing therapies → Resistant therapies (ifmultiple therapies exist within any of thesecategories, they are listed in no particular order).

Clinical TrialsPediatric trial qualification → GeographicalProximity → Later trial phase.

LEVEL OF EVIDENCE NOLEVEL OF EVIDENCE NOT PROT PROVIDEDVIDEDDrugs with potential clinical benefit (or potentiallack of clinical benefit) are not evaluated forsource or level of published evidence.

NO GUNO GUARANTEE OF CLINICAL BENEFITARANTEE OF CLINICAL BENEFITFoundation Medicine makes no promises orguarantees that a particular drug will be effectivein the treatment of disease of any patient. Thisreport also makes no promises or guarantees thata drug with potential lack of clinical benefit willin fact provide no clinical benefit.

NO GUNO GUARANTEE OF REIMBURSEMENTARANTEE OF REIMBURSEMENTFoundation Medicine makes no promises orguarantees that a healthcare provider, insurer orother third party payor, whether private orgovernmental, will reimburse a patient for thecost of FoundationOne CDx.

TREATREATMENT DECISIONS ARETMENT DECISIONS ARERESPONSIBILITY OF PHYRESPONSIBILITY OF PHYSICIANSICIANDrugs referenced may not be suitable for aparticular patient. The selection of any, all ornone of the drugs associated with potentialclinical benefit (or potential lack of clinicalbenefit) resides with the physician. Indeed, theinformation in this Report must be considered inconjunction with all other relevant informationregarding a particular patient, before the patient’streating physician recommends a course oftreatment. Decisions on patient care andtreatment must be based on the independentmedical judgment of the treating physician,taking into consideration all applicableinformation concerning the patient’s condition,such as patient and family history, physicalexaminations, information from other diagnostictests, and patient preferences, in accordance withthe standard of care in a given community. Atreating physician’s decisions should not be basedon a single test, such as this Test, or theinformation contained in this Report.

Genomic Findings with Evidence of Clinical SignificanceGenomic findings listed at Level 2 are associatedwith clinical significance. Clinical significance maybe indicated by evidence of therapeutic sensitivityor resistance and/or diagnostic, prognostic or otherclinically relevant implications. Included in thiscategory will be findings associated with clinicalvalidity as supported by professional guidelinesand/or peer-reviewed publications.

Genomic Findings with Potential Clinical SignificanceGenomic findings listed at Level 3 are cancer-relatedmutations and biomarkers with potential clinicalsignificance. These include findings in genes knownto be associated with cancer and are supported byevidence from publicly available databases, and/orpeer-reviewed publications.

A Fluid Approach to Reporting LevelsAs additional information becomes available, asrecognized by the clinical community (professionalguidelines and/or peer-reviewed publications),findings may move between Levels 2 and 3 inaccordance with the above descriptions.

SELECT ABBREVIASELECT ABBREVIATIONSTIONS

ABBREVIATION DEFINITION

CR Complete response

DCR Disease control rate

DNMT DNA methyltransferase

HR Hazard ratio

ITD Internal tandem duplication

MMR Mismatch repair

muts/Mb Mutations per megabase

NOS Not otherwise specified

ORR Objective response rate

OS Overall survival

PD Progressive disease

PFS Progression-free survival

PR Partial response

SD Stable disease

TKI Tyrosine kinase inhibitor


Lung adenocarcinoma

InfInformation Pormation Prroovided as a Pvided as a Prrofofesessional Servicsional ServiceeAPPENDIXAPPENDIX





SAMPLE

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Lung adenocarcinoma

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9988 Li et al., 2015; ASCO Abstract 8090

9999 Ou SH, Kwak EL, Siwak-Tapp C, et al. (2011) Activity ofcrizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphomakinase (ALK) inhibitor, in a non-small cell lung cancerpatient with de novo MET amplification. J ThoracOncol 6(5):942-6


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100100 Schwab R, Petak I, Kollar M, et al. (2014) Major partialresponse to crizotinib, a dual MET/ALK inhibitor, in asquamous cell lung (SCC) carcinoma patient with denovo c-MET amplification in the absence of ALKrearrangement. Lung Cancer 83(1):109-11

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110110 Mendenhall MA, Goldman JW (2015) MET-MutatedNSCLC with Major Response to Crizotinib. J ThoracOncol 10(5):e33-4

111111 Stein MN, Hirshfield KM, Zhong H, et al. (2015)Response to Crizotinib in a Patient with MET-mutantPapillary Renal Cell Cancer After Progression onTivantinib. Eur Urol 67(2):353-4

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125125 Kollmannsberger et al., 2015; ASCO Abstract 2589

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130130 Oliner et al., 2012; ASCO Abstract 4005

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131377 Chen YT, Chang JW, Liu HP, et al. (2011) Clinicalimplications of high MET gene dosage in non-smallcell lung cancer patients without previous tyrosinekinase inhibitor treatment. J Thorac Oncol6(12):2027-35

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114646 Gopalan et al., 2014; ASCO Abstract 8077

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224499 Bridges KA, Hirai H, Buser CA, et al. (2011) MK-1775, anovel Wee1 kinase inhibitor, radiosensitizesp53-defective human tumor cells. Clin Cancer Res17(17):5638-48

250250 Rajeshkumar NV, De Oliveira E, Ottenhof N, et al.(2011) MK-1775, a potent Wee1 inhibitor, synergizeswith gemcitabine to achieve tumor regressions,selectively in p53-deficient pancreatic cancerxenografts. Clin Cancer Res 17(9):2799-806

252511 Osman AA, Monroe MM, Ortega Alves MV, et al.(2015) Wee-1 kinase inhibition overcomes cisplatinresistance associated with high-risk TP53 mutationsin head and neck cancer through mitotic arrestfollowed by senescence. Mol Cancer Ther14(2):608-19

252522 Gourley et al., 2016; ASCO Abstract 5571

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254254 Mohell N, Alfredsson J, Fransson Å, et al. (2015)APR-246 overcomes resistance to cisplatin anddoxorubicin in ovarian cancer cells. Cell Death Dis6:e1794

252555 Fransson Å, Glaessgen D, Alfredsson J, et al. (2016)Strong synergy with APR-246 and DNA-damagingdrugs in primary cancer cells from patients with TP53mutant High-Grade Serous ovarian cancer. J OvarianRes 9(1):27

256256 Xu L, Huang CC, Huang W, et al. (2002) Systemictumor-targeted gene delivery by anti-transferrinreceptor scFv-immunoliposomes. Mol Cancer Ther1(5):337-46

252577 Xu L, Tang WH, Huang CC, et al. (2001) Systemic p53gene therapy of cancer with immunolipoplexestargeted by anti-transferrin receptor scFv. Mol Med7(10):723-34

258258 Camp ER, Wang C, Little EC, et al. (2013) Transferrinreceptor targeting nanomedicine delivering wild-type p53 gene sensitizes pancreatic cancer togemcitabine therapy. Cancer Gene Ther 20(4):222-8

252599 Kim SS, Rait A, Kim E, et al. (2015) A tumor-targetingp53 nanodelivery system limits chemoresistance totemozolomide prolonging survival in a mouse modelof glioblastoma multiforme. Nanomedicine11(2):301-11

226060 Pirollo KF, Nemunaitis J, Leung PK, et al. (2016) Safetyand Efficacy in Advanced Solid Tumors of a TargetedNanocomplex Carrying the p53 Gene Used inCombination with Docetaxel: A Phase 1b Study. MolTher 24(9):1697-706

226611 Hajdenberg et al., 2012; ASCO Abstract e15010

226622 Leijen S, van Geel RM, Pavlick AC, et al. (2016) Phase IStudy Evaluating WEE1 Inhibitor AZD1775 AsMonotherapy and in Combination With Gemcitabine,Cisplatin, or Carboplatin in Patients With AdvancedSolid Tumors. J Clin Oncol ePub Sep 2016

226633 Oza et al., 2015; ASCO Abstract 5506

226644 Leijen et al., 2015; ASCO Abstract 2507

226565 Ma CX, Cai S, Li S, et al. (2012) Targeting Chk1 inp53-deficient triple-negative breast cancer istherapeutically beneficial in human-in-mouse tumormodels. J Clin Invest 122(4):1541-52

226666 Kumar et al., 2012; AACR Abstract 2874

226677 Mogi A, Kuwano H (2011) TP53 mutations in nonsmallcell lung cancer. J Biomed Biotechnol 2011:583929

226868 Tekpli X, Landvik NE, Skaug V, et al. (2013) Functionaleffect of polymorphisms in 15q25 locus on CHRNA5mRNA, bulky DNA adducts and TP53 mutations. Int JCancer 132(8):1811-20

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227700 Maeng CH, Lee HY, Kim YW, et al. (2013) High-throughput molecular genotyping for small biopsysamples in advanced non-small cell lung cancerpatients. Anticancer Res 33(11):5127-33

227711 Itakura M, Terashima Y, Shingyoji M, et al. (2013) HighCC chemokine receptor 7 expression improvespostoperative prognosis of lung adenocarcinomapatients. Br J Cancer 109(5):1100-8

227722 Seo JS, Ju YS, Lee WC, et al. (2012) The transcriptionallandscape and mutational profile of lungadenocarcinoma. Genome Res 22(11):2109-19

227373 Brown CJ, Lain S, Verma CS, et al. (2009) Awakeningguardian angels: drugging the p53 pathway. Nat RevCancer 9(12):862-73

227744 Joerger AC, Fersht AR (2008) Structural biology ofthe tumor suppressor p53. Annu Rev Biochem77:557-82

227755 Kato S, Han SY, Liu W, et al. (2003) Understanding thefunction-structure and function-mutationrelationships of p53 tumor suppressor protein byhigh-resolution missense mutation analysis. ProcNatl Acad Sci USA 100(14):8424-9

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228181 Kleihues P, Schäuble B, zur Hausen A, et al. (1997)Tumors associated with p53 germline mutations: asynopsis of 91 families. Am J Pathol 150(1):1-13

228822 Gonzalez KD, Noltner KA, Buzin CH, et al. (2009)Beyond Li Fraumeni Syndrome: clinicalcharacteristics of families with p53 germlinemutations. J Clin Oncol 27(8):1250-6

228383 Lalloo F, Varley J, Ellis D, et al. (2003) Prediction ofpathogenic mutations in patients with early-onsetbreast cancer by family history. Lancet361(9363):1101-2

228844 Cappuzzo F, Finocchiaro G, Grossi F, et al. (2015)Phase II study of afatinib, an irreversible ErbB familyblocker, in EGFR FISH-positive non-small-cell lungcancer. J Thorac Oncol 10(4):665-72

228585 Kwak EL, Shapiro GI, Cohen SM, et al. (2013) Phase 2trial of afatinib, an ErbB family blocker, in solidtumors genetically screened for target activation.Cancer 119(16):3043-51

228686 Li M, Zhang Z, Li X, et al. (2014) Whole-exome andtargeted gene sequencing of gallbladder carcinomaidentifies recurrent mutations in the ErbB pathway.Nat Genet 46(8):872-6

228877 Wu YL, Zhou C, Hu CP, et al. (2014) Afatinib versuscisplatin plus gemcitabine for first-line treatment ofAsian patients with advanced non-small-cell lungcancer harbouring EGFR mutations (LUX-Lung 6): anopen-label, randomised phase 3 trial. Lancet Oncol15(2):213-22

228888 Yang JC, Wu YL, Schuler M, et al. (2015) Afatinibversus cisplatin-based chemotherapy for EGFRmutation-positive lung adenocarcinoma (LUX-Lung 3and LUX-Lung 6): analysis of overall survival datafrom two randomised, phase 3 trials. Lancet OncolePub Jan 2015

228899 Soria JC, Felip E, Cobo M, et al. (2015) Afatinib versuserlotinib as second-line treatment of patients withadvanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase3 trial. Lancet Oncol ePub Jul 2015

290290 Paz-Ares L, Tan EH, O'Byrne K, et al. (2017) Afatinibversus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overallsurvival data from the phase IIb LUX-Lung 7 trial. AnnOncol 28(2):270-277

291291 Miller VA, Hirsh V, Cadranel J, et al. (2012) Afatinibversus placebo for patients with advanced,metastatic non-small-cell lung cancer after failure oferlotinib, gefitinib, or both, and one or two lines ofchemotherapy (LUX-Lung 1): a phase 2b/3randomised trial. Lancet Oncol 13(5):528-38

292922 Chen X, Zhu Q, Zhu L, et al. (2013) Clinicalperspective of afatinib in non-small cell lung cancer.Lung Cancer 81(2):155-61

292933 Katakami N, Atagi S, Goto K, et al. (2013) LUX-Lung 4:a phase II trial of afatinib in patients with advancednon-small-cell lung cancer who progressed duringprior treatment with erlotinib, gefitinib, or both. JClin Oncol 31(27):3335-41

292944 Landi L, Tiseo M, Chiari R, et al. (2014) Activity of theEGFR-HER2 Dual Inhibitor Afatinib in EGFR-MutantLung Cancer Patients With Acquired Resistance toReversible EGFR Tyrosine Kinase Inhibitors. Clin LungCancer 15(6):411-417.e4


Lung adenocarcinoma



Electronically signed by Shakti Ramkissoon, M.D., Ph.D. | Jeffrey Ross, M.D., Medical DirectoFoundation Medicine, Inc. | 1.888.988.3639



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292955 De Grève J, Moran T, Graas MP, et al. (2015) Phase IIstudy of afatinib, an irreversible ErbB family blocker,in demographically and genotypically defined lungadenocarcinoma. Lung Cancer 88(1):63-9

296296 Yang JC, Sequist LV, Geater SL, et al. (2015) Clinicalactivity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFRmutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet OncolePub Jun 2015

292977 Wu SG, Liu YN, Tsai MF, et al. (2016) The mechanismof acquired resistance to irreversible EGFR tyrosinekinase inhibitor-afatinib in lung adenocarcinomapatients. Oncotarget ePub Feb 2016

292988 Kim Y, Ko J, Cui Z, et al. (2012) The EGFR T790Mmutation in acquired resistance to an irreversiblesecond-generation EGFR inhibitor. Mol Cancer Ther11(3):784-91

299299 Tanaka K, Nosaki K, Otsubo K, et al. (2017)Acquisition of the T790M resistance mutation duringafatinib treatment in EGFR tyrosine kinase inhibitor-naïve patients with non-small cell lung cancerharboring EGFR mutations. Oncotarget8(40):68123-68130

300300 Janjigian YY, Smit EF, Groen HJ, et al. (2014) DualInhibition of EGFR with Afatinib and Cetuximab inKinase Inhibitor-Resistant EGFR-Mutant Lung Cancerwith and without T790M Mutations. Cancer DiscovePub Jul 2014

303011 Ribeiro Gomes J, Cruz MR (2015) Combination ofafatinib with cetuximab in patients with EGFR-mutant non-small-cell lung cancer resistant to EGFRinhibitors. Onco Targets Ther 8:1137-42

303022 Castellanos EH, Rivera G, Wakelee H, et al. (2015)Overcoming Resistance Without the Risk of Reaction:Use of Afatinib and Panitumumab in Two Cases ofEpidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer With T790M Mutations. ClinLung Cancer ePub Mar 2015

303033 Schuler M, Yang JC, Park K, et al. (2016) Afatinibbeyond progression in patients with non-small-celllung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung5 trial. Ann Oncol 27(3):417-23

304304 Horn L, Gettinger S, Camidge DR, et al. (2017)Continued use of afatinib with the addition ofcetuximab after progression on afatinib in patientswith EGFR mutation-positive non-small-cell lungcancer and acquired resistance to gefitinib orerlotinib. Lung Cancer 113:51-58

305305 Camidge et al., 2014; ASCO Abstract 8001

306306 Jorge SE, Schulman S, Freed JA, et al. (2015)Responses to the multitargeted MET/ALK/ROS1inhibitor crizotinib and co-occurring mutations inlung adenocarcinomas with MET amplification orMET exon 14 skipping mutation. Lung Cancer90(3):369-74

303077 Zhang Y, Wang W, Wang Y, et al. (2016) Response toCrizotinib Observed in Lung Adenocarcinoma withMET Copy Number Gain but without a High-LevelMET/CEP7 Ratio, MET Overexpression, or Exon 14Splicing Mutations. J Thorac Oncol 11(5):e59-62

308308 Caparica R, Yen CT, Coudry R, et al. (2017) Responsesto Crizotinib Can Occur in High-Level MET-AmplifiedNon-Small Cell Lung Cancer Independent of METExon 14 Alterations. J Thorac Oncol 12(1):141-144

309309 York ER, Varella-Garcia M, Bang TJ, et al. (2017)Tolerable and Effective Combination of Full-DoseCrizotinib and Osimertinib Targeting METAmplification Sequentially Emerging after T790MPositivity in EGFR-Mutant Non-Small Cell LungCancer. J Thorac Oncol ePub Mar 2017

310310 Drilon et al., 2016; ASCO Abstract 108

311311 Schrock AB, Frampton GM, Suh J, et al. (2016)Characterization of 298 Patients with Lung CancerHarboring MET Exon 14 Skipping Alterations. J ThoracOncol ePub Jun 2016

312312 Mahjoubi L, Gazzah A, Besse B, et al. (2016) A never-smoker lung adenocarcinoma patient with a METexon 14 mutation (D1028N) and a rapid partialresponse after crizotinib. Invest New Drugs34(3):397-8

313313 Benderra MA, Aspeslagh S, Postel-Vinay S, et al.(2016) Acquired EGFR Mutation as the PotentialResistance Driver to Crizotinib in a MET-MutatedTumor. J Thorac Oncol 11(2):e21-3

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316316 Dahabreh IJ, Linardou H, Kosmidis P, et al. (2011) EGFRgene copy number as a predictive biomarker forpatients receiving tyrosine kinase inhibitortreatment: a systematic review and meta-analysis innon-small-cell lung cancer. Ann Oncol 22(3):545-52

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318318 Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al.(2005) Erlotinib in previously treated non-small-celllung cancer. N Engl J Med 353(2):123-32

319319 Cappuzzo F, Ciuleanu T, Stelmakh L, et al. (2010)Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised,placebo-controlled phase 3 study. Lancet Oncol11(6):521-9

332020 Garassino MC, Martelli O, Broggini M, et al. (2013)Erlotinib versus docetaxel as second-line treatmentof patients with advanced non-small-cell lung cancerand wild-type EGFR tumours (TAILOR): a randomisedcontrolled trial. Lancet Oncol 14(10):981-8

332211 Kawaguchi T, Ando M, Asami K, et al. (2014)Randomized phase III trial of erlotinib versusdocetaxel as second- or third-line therapy in patientswith advanced non-small-cell lung cancer: Docetaxeland Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol32(18):1902-8

332222 Liu J, Sheng Z, Zhang Y, et al. (2016) The Efficacy ofEpidermal Growth Factor Receptor Tyrosine KinaseInhibitors for Molecularly Selected Patients withNon-Small Cell Lung Cancer: A Meta-Analysis of 30Randomized Controlled Trials. Target Oncol11(1):49-58

332233 Reck M, van Zandwijk N, Gridelli C, et al. (2010)Erlotinib in advanced non-small cell lung cancer:efficacy and safety findings of the global phase IVTarceva Lung Cancer Survival Treatment study. JThorac Oncol 5(10):1616-22

332244 Fukuoka M, Wu YL, Thongprasert S, et al. (2011)Biomarker analyses and final overall survival resultsfrom a phase III, randomized, open-label, first-linestudy of gefitinib versus carboplatin/paclitaxel inclinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol29(21):2866-74

332525 Mok TS, Wu YL, Thongprasert S, et al. (2009)Gefitinib or carboplatin-paclitaxel in pulmonaryadenocarcinoma. N Engl J Med 361(10):947-57

332266 Cross DA, Ashton SE, Ghiorghiu S, et al. (2014)AZD9291, an Irreversible EGFR TKI, OvercomesT790M-Mediated Resistance to EGFR Inhibitors inLung Cancer. Cancer Discov 4(9):1046-1061

332277 Mok TS, Wu YL, Ahn MJ, et al. (2016) Osimertinib orPlatinum-Pemetrexed in EGFR T790M-Positive LungCancer. N Engl J Med ePub Dec 2016

332288 Yang et al., 2016; ELCC Abstract LBA2_PR

332929 Goss G, Tsai CM, Shepherd FA, et al. (2016)Osimertinib for pretreated EGFR Thr790Met-positiveadvanced non-small-cell lung cancer (AURA2): amulticentre, open-label, single-arm, phase 2 study.Lancet Oncol 17(12):1643-1652

333030 Ramalingnam et al., 2017; ESMO Abstract LBA2_PR

333131 Ramalingam SS, Yang JC, Lee CK, et al. (2017)Osimertinib As First-Line Treatment of EGFRMutation-Positive Advanced Non-Small-Cell LungCancer. J Clin Oncol :JCO2017747576

333322 Ramalingam et al., 2015; ASCO Abstract 2509

333333 Miyauchi E, Ichinose M, Inoue A (2017) SuccessfulOsimertinib Rechallenge in a Patient with T790M-Mutant Non-Small Cell Lung Cancer afterOsimertinib-Induced Interstitial Lung Disease. JThorac Oncol 12(5):e59-e61

333434 Yoshida H, Kim YH (2017) Successful OsimertinibRechallenge after Severe Osimertinib-InducedHepatotoxicity. J Thorac Oncol 12(5):e61-e63

333535 Junttila TT, Li G, Parsons K, et al. (2011) Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action oftrastuzumab and efficiently inhibits growth oflapatinib insensitive breast cancer. Breast Cancer ResTreat 128(2):347-56

333636 Lewis Phillips GD, Li G, Dugger DL, et al. (2008)Targeting HER2-positive breast cancer withtrastuzumab-DM1, an antibody-cytotoxic drugconjugate. Cancer Res 68(22):9280-90

333377 Erickson HK, Park PU, Widdison WC, et al. (2006)Antibody-maytansinoid conjugates are activated intargeted cancer cells by lysosomal degradation andlinker-dependent intracellular processing. CancerRes 66(8):4426-33

333838 Weiler D, Diebold J, Strobel K, et al. (2015) Rapidresponse to trastuzumab emtansine in a patient withHER2-driven lung cancer. J Thorac Oncol 10(4):e16-7

333939 Mazières J, Barlesi F, Filleron T, et al. (2015) Lungcancer patients with HER2 mutations treated withchemotherapy and HER2-targeted drugs: Resultsfrom the European EUHER2 cohort. Ann Oncol ePubNov 2015


Lung adenocarcinoma






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340340 Krop IE, Kim SB, González-Martín A, et al. (2014)Trastuzumab emtansine versus treatment ofphysician's choice for pretreated HER2-positiveadvanced breast cancer (TH3RESA): a randomised,open-label, phase 3 trial. Lancet Oncol 15(7):689-99

343411 Verma S, Miles D, Gianni L, et al. (2012) Trastuzumabemtansine for HER2-positive advanced breast cancer.N Engl J Med 367(19):1783-91

342342 Welslau M, Diéras V, Sohn JH, et al. (2014) Patient-reported outcomes from EMILIA, a randomized phase3 study of trastuzumab emtansine (T-DM1) versuscapecitabine and lapatinib in human epidermalgrowth factor receptor 2-positive locally advanced ormetastatic breast cancer. Cancer 120(5):642-51

343343 Krop IE, LoRusso P, Miller KD, et al. (2012) A phase IIstudy of trastuzumab emtansine in patients withhuman epidermal growth factor receptor 2-positivemetastatic breast cancer who were previouslytreated with trastuzumab, lapatinib, ananthracycline, a taxane, and capecitabine. J ClinOncol 30(26):3234-41

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345345 Klempner SJ, Borghei A, Hakimian B, et al. (2016)Brief Report: Intracranial Activity of Cabozantinib inMET exon14 Positive NSCLC with Brain Metastases. JThorac Oncol ePub Sep 2016

346346 Drilon A, Rekhtman N, Arcila M, et al. (2016)Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. LancetOncol 17(12):1653-1660

343477 Drilon A, Wang L, Hasanovic A, et al. (2013) Responseto Cabozantinib in patients with RET fusion-positivelung adenocarcinomas. Cancer Discov 3(6):630-5

343488 Gautschi et al., 2016; ASCO Abstract 9014

343499 Mukhopadhyay S, Pennell NA, Ali SM, et al. (2014)RET-Rearranged Lung Adenocarcinomas withLymphangitic Spread, Psammoma Bodies, andClinical Responses to Cabozantinib. J Thorac Oncol9(11):1714-1719

350350 Hellerstedt et al., 2012; ASCO Abstract 7514

353511 Neal JW, Dahlberg SE, Wakelee HA, et al. (2016)Erlotinib, cabozantinib, or erlotinib plus cabozantinibas second-line or third-line treatment of patientswith EGFR wild-type advanced non-small-cell lungcancer (ECOG-ACRIN 1512): a randomised, controlled,open-label, multicentre, phase 2 trial. Lancet Oncol17(12):1661-1671

353522 Jiang Z, Li C, Li F, et al. (2013) EGFR gene copy numberas a prognostic marker in colorectal cancer patientstreated with cetuximab or panitumumab: asystematic review and meta analysis. PLoS ONE8(2):e56205

353533 Licitra L, Mesia R, Rivera F, et al. (2011) Evaluation ofEGFR gene copy number as a predictive biomarker forthe efficacy of cetuximab in combination withchemotherapy in the first-line treatment of recurrentand/or metastatic squamous cell carcinoma of thehead and neck: EXTREME study. Ann Oncol22(5):1078-87

354354 Ramalingam SS, Kotsakis A, Tarhini AA, et al. (2013) Amulticenter phase II study of cetuximab incombination with chest radiotherapy andconsolidation chemotherapy in patients with stage IIInon-small cell lung cancer. Lung Cancer 81(3):416-21

353555 Kim ES, Neubauer M, Cohn A, et al. (2013) Docetaxelor pemetrexed with or without cetuximab inrecurrent or progressive non-small-cell lung cancerafter platinum-based therapy: a phase 3, open-label,randomised trial. Lancet Oncol 14(13):1326-36

356356 Wheler JJ, Tsimberidou AM, Falchook GS, et al. (2013)Combining erlotinib and cetuximab is associatedwith activity in patients with non-small cell lungcancer (including squamous cell carcinomas) andwild-type EGFR or resistant mutations. Mol CancerTher 12(10):2167-75

353577 Ross HJ, Blumenschein GR, Aisner J, et al. (2010)Randomized phase II multicenter trial of twoschedules of lapatinib as first- or second-linemonotherapy in patients with advanced ormetastatic non-small cell lung cancer. Clin CancerRes 16(6):1938-49

358358 Diaz R, Nguewa PA, Parrondo R, et al. (2010)Antitumor and antiangiogenic effect of the dual EGFRand HER-2 tyrosine kinase inhibitor lapatinib in alung cancer model. BMC Cancer 10:188

353599 Burris HA, Taylor CW, Jones SF, et al. (2009) A phase Iand pharmacokinetic study of oral lapatinibadministered once or twice daily in patients withsolid malignancies. Clin Cancer Res 15(21):6702-8

360360 Crawford J, Swanson P, Schwarzenberger P, et al.(2013) A phase 2 randomized trial of paclitaxel andcarboplatin with or without panitumumab for first-line treatment of advanced non-small-cell lungcancer. J Thorac Oncol 8(12):1510-8

363611 Schuette W, Behringer D, Stoehlmacher J, et al. (2015)CHAMP: A Phase II Study of Panitumumab WithPemetrexed and Cisplatin Versus Pemetrexed andCisplatin in the Treatment of Patients WithAdvanced-Stage Primary Nonsquamous Non-Small-Cell Lung Cancer With Particular Regard to the KRASStatus. Clin Lung Cancer ePub Jun 2015

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363633 Swain SM, Kim SB, Cortés J, et al. (2013) Pertuzumab,trastuzumab, and docetaxel for HER2-positivemetastatic breast cancer (CLEOPATRA study): overallsurvival results from a randomised, double-blind,placebo-controlled, phase 3 study. Lancet Oncol14(6):461-71

363644 Agus DB, Gordon MS, Taylor C, et al. (2005) Phase Iclinical study of pertuzumab, a novel HERdimerization inhibitor, in patients with advancedcancer. J Clin Oncol 23(11):2534-43

365365 Yamamoto N, Yamada Y, Fujiwara Y, et al. (2009)Phase I and pharmacokinetic study of HER2-targetedrhuMAb 2C4 (Pertuzumab, RO4368451) in Japanesepatients with solid tumors. Jpn J Clin Oncol39(4):260-6

366366 Herbst RS, Davies AM, Natale RB, et al. (2007)Efficacy and safety of single-agent pertuzumab, ahuman epidermal receptor dimerization inhibitor, inpatients with non small cell lung cancer. Clin CancerRes 13(20):6175-81

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368368 Punnoose EA, Atwal S, Liu W, et al. (2012) Evaluationof circulating tumor cells and circulating tumor DNAin non-small cell lung cancer: association withclinical endpoints in a phase II clinical trial ofpertuzumab and erlotinib. Clin Cancer Res18(8):2391-401

363699 Hughes B, Mileshkin L, Townley P, et al. (2014)Pertuzumab and Erlotinib in Patients With RelapsedNon-Small Cell Lung Cancer: A Phase II Study Using18F-Fluorodeoxyglucose Positron EmissionTomography/Computed Tomography Imaging.Oncologist 19(2):175-6

337700 Lara PN, Laptalo L, Longmate J, et al. (2004)Trastuzumab plus docetaxel in HER2/neu-positivenon-small-cell lung cancer: a California CancerConsortium screening and phase II trial. Clin LungCancer 5(4):231-6

337711 Krug LM, Miller VA, Patel J, et al. (2005) Randomizedphase II study of weekly docetaxel plus trastuzumabversus weekly paclitaxel plus trastuzumab inpatients with previously untreated advancednonsmall cell lung carcinoma. Cancer104(10):2149-55

337722 Hainsworth et al., 2016; ASCO Abstract LBA11511

337373 Cappuzzo F, Bemis L, Varella-Garcia M (2006) HER2mutation and response to trastuzumab therapy innon-small-cell lung cancer. N Engl J Med354(24):2619-21

337744 Mazières J, Peters S, Lepage B, et al. (2013) Lungcancer that harbors an HER2 mutation:epidemiologic characteristics and therapeuticperspectives. J Clin Oncol 31(16):1997-2003

337755 Rugo et al., 2016; ASCO Abstract LBA503

337766 Waller et al., 2016; ASCO Abstract 583

337777 Audran et al., 2017; ASCO-SITC Clinical Immuno-Oncology Symposium Abstract 10


Lung adenocarcinoma






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exon 19 deletion (t751 i759>s) gilotrif® (afatinib) sample · 2020. 3. 26. · egfr exon 19...

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